Compounds and methods for antiviral treatment

ABSTRACT

Compounds and pharmaceutically acceptable salts and esters and compositions thereof, for treating viral infections are provided. The compounds and compositions are useful for treating Pneumovirinae virus infections. The compounds, compositions, and methods provided are particularly useful for the treatment of Human respiratory syncytial virus infections.

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority of U.S.Application Ser. No. 61/625,480, filed Apr. 17, 2012. The content ofthis provisional application is hereby incorporated herein in itsentirety.

BACKGROUND OF THE INVENTION

Pneumovirinae viruses are negative-sense, single-stranded, RNA virusesthat are responsible for many prevalent human and animal diseases. ThePneumovirinae sub-family of viruses is a part of the familyParamyxoviridae and includes human respiratory syncytial virus (HRSV).Almost all children will have had an HRSV infection by their secondbirthday. HRSV is the major cause of lower respiratory tract infectionsin infancy and childhood with 0.5% to 2% of those infected requiringhospitalization. The elderly and adults with chronic heart, lung diseaseor those that are immunosuppressed also have a high risk for developingsevere HRSV disease (www.cdc.gov/rsv/index.html). No vaccine to preventHRSV infection is currently available. The monoclonal antibodypalivizumab is available for immunoprophylaxis, but its use isrestricted to infants at high risk, e.g., premature infants or thosewith either congenital heart or lung disease, and the cost for generaluse is often prohibitive. In addition, the nucleoside analog ribavirinhas been approved as the only antiviral agent to treat HRSV infectionsbut has limited efficacy. Therefore, there is a need foranti-Pneumovirinae therapeutics.

SUMMARY OF THE INVENTION

Provided herein are methods and compounds for the treatment ofinfections caused by the Pneumovirinae virus family.

Accordingly, one embodiment provides a compound of formula I:

or a pharmaceutically acceptable salt thereof;

wherein:

a) Y¹ is N, NH or CH, Y² is C, Y³ is N or CR^(8′), Y⁴ is N or C and Y⁵is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently N, NH or NR^(2′); or

-   -   b) Y¹ is N, NH or CH, Y² is N or C, Y³ is N or CR^(8′), Y⁴ is N        or C, and Y⁵ is N or NR^(2′), wherein at least two of Y¹, Y²,        Y³, Y⁴ and Y⁵ are independently N, NH or NR^(2′); or    -   c) Y¹ is N, NH or CH, Y² is N or C, Y³ is CR^(8′), Y⁴ is N or C,        and Y⁵ is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³,        Y⁴ and Y⁵ are independently N, NH or NR^(2′);    -   the dashed bonds ---- are selected from single bonds and double        bonds so as to provide an aromatic ring system;

A is —(CR⁴R^(4′))_(n)— wherein any one CR⁴ R^(4′) of said—(CR⁴R^(4′))_(n)— may be optionally replaced with —O—, —S—, —S(O)_(p)—,NH or NR^(a);

n is 3, 4, 5 or 6;

each p is 1 or 2;

Ar is a C₂-C₂₀ heterocyclyl group or a C₆-C₂₀ aryl group, wherein theC₂-C₂₀ heterocyclyl group or the C₆-C₂₀ aryl group is optionallysubstituted with 1 to 5 R⁶;

X is —C(R¹³)(R¹⁴)—, —N(CH₂R¹⁴)— or —NH—, or X is absent;

R¹ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, SR¹¹, —S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R² is H, CN, NO₂, halogen or (C₁-C₈)alkyl;

R^(2′) is H or (C₁-C₈)alkyl;

R³ is H, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, —SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R^(3′) is H, —OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

-   -   each R⁴ is independently H, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹,        —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, SR¹¹,        —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,        —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,        —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹²,        halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,        aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀        heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or        (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; and

each R^(4′) is independently H, OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

or two R⁴ on adjacent carbon atoms, when taken together, may form adouble bond between the two carbons to which they are attached or mayform a (C₃-C₇)cycloalkyl ring wherein one carbon atom of said(C₃-C₇)cycloalkyl ring may be optionally replaced by —O—, —S—,—S(O)_(p)—, —NH— or —NR^(a)—;

or two R⁴ on non-adjacent carbon atoms, when taken together, may form a(C₃-C₇)cycloalkyl ring wherein one carbon atom of said (C₃-C₇)cycloalkylring may be optionally replaced by —O—, —S—, —S(O)_(p)—, —NH— or—NR^(a)—;

or two R⁴ and two R^(4′) on adjacent carbon atoms, when taken together,may form an optionally substituted C₆ aryl ring;

or one R⁴ and one R^(4′) on the same carbon atom, when taken together,may form a (C₃-C₇)cycloalkyl ring wherein one carbon atom of said(C₃-C₇)cycloalkyl ring may be optionally replaced by —O—, —S—,—S(O)_(p)—, —NH— or —NR^(a)—;

each R⁵ is independently H, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹,—NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, —SR¹¹, —S(O)_(p)R^(a),—NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹²,—NR¹¹C(═NR¹¹)NR¹¹R¹², halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

each R^(5′) is independently H, —OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

each R⁶ is independently H, oxo, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹,—NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, SR¹¹, —S(O)_(p)R^(a),—NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹²,—NR¹¹C(═NR¹¹)NR¹¹R¹², halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

or two R⁶ on adjacent carbon atoms, when taken together, may form a(C₃-C₇)cycloalkyl ring wherein one carbon atom of said (C₃-C₇)cycloalkylring may be optionally replaced by —O—, —S—, —S(O)_(p)—, —NH— or—NR^(a)—;

or any R⁶ adjacent to the obligate carbonyl group of said Ar, when takentogether with R³, may form a bond or a —(CR⁵R^(5′))_(m)— group wherein mis 1 or 2;

or any R⁶ adjacent to the obligate carbonyl group of said Ar, when takentogether with R² or R^(2′) may form a bond;

R⁷ is H, OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, —SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R⁸ is H, —OR¹¹, —NR¹¹R¹², NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, —SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R^(8′) is H, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹,—NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹),—SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹²,—NR¹¹C(═NR¹¹)NR¹¹R¹², halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

-   -   each R^(a) is independently (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl,        C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,        (C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl wherein any        (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl        of R^(a) is optionally substituted with one or more OH, NH₂,        CO₂H, C₂-C₂₀ heterocyclyl, and wherein any aryl(C₁-C₈)alkyl,        C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, (C₃-C₇)cycloalkyl or        (C₃-C₇)cycloalkyl(C₁-C₈)alkyl of R^(a) is optionally substituted        with one or more —OH, —NH₂, CO₂H, C₂-C₂₀ heterocyclyl or        (C₁-C₈)alkyl;    -   each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl,        (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl,        C₂-C₂₀ heterocyclyl, (C₃-C₇)cycloalkyl,        (C₃-C₇)cycloalkyl(C₁-C₈)alkyl, —C(═O)R^(a) or —S(O)_(p)R^(a); or        when R¹¹ and R¹² are attached to a nitrogen they may optionally        be taken together with the nitrogen to which they are both        attached to form a 3 to 7 membered heterocyclic ring wherein any        one carbon atom of said heterocyclic ring can optionally be        replaced with —O—, —S—, —S(O)_(p)—, —NH—, —NR^(a)- or —C(O)—;

R¹³ is H or (C₁-C₈)alkyl;

R¹⁴ is H, (C₁-C₈)alkyl, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,NR¹¹C(O)NR¹¹R¹², NR¹¹S(O)_(p)R^(a), —NR¹¹S(O)_(p)(OR¹¹) orNR¹¹SO_(p)NR¹¹R¹²; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl of each R¹, R², R^(2′), R³, R^(3′), R⁴,R^(4′), R⁵, R^(5′), R⁶, R⁷, R⁸, R^(8′), R¹¹ or R¹² is independently,optionally substituted with one or more oxo, halogen, hydroxy, —NH₂, CN,N₃, —N(R^(a))₂, —NHR^(a), —SH, —SR^(a), —S(O)_(p)R^(a), —OR^(a),(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR^(a)S(O)_(p)N(R^(a))₂, —NR^(a)S(O)pNH₂, —NHS(O)_(p)NHR^(a), —NHS(O)_(p)N(R^(a))₂, —NHS(O)_(p)NH₂,—OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).

One embodiment provides a compound of formulas 1-103 (i.e., compounds1-103 as described in examples 117-218), or a salt or ester thereof.

One embodiment provides a compound of formula I (including compounds104-122 of examples 219-237) or a stereoisomer (e.g., enantiomer,diasteromer, atropisomer) or a salt or ester thereof or a compound offormulas 1-103 or a stereoisomer (e.g., enantiomer, diasteromer,atropisomer) or a salt or ester thereof.

One embodiment provides a pharmaceutical composition comprising acompound disclosed herein or a pharmaceutically acceptable salt or esterthereof (e.g., a compound of formula I or a pharmaceutically acceptablesalt thereof or ester thereof, or a compound of formulas 1-103 or apharmaceutically acceptable salt or ester thereof), and apharmaceutically acceptable carrier.

One embodiment provides a method of treating a Pneumovirinae infectionin a mammal (e.g., a human) in need thereof by administering atherapeutically effective amount of a compound disclosed herein or apharmaceutically acceptable salt or ester thereof (e.g., a compound offormula I or a pharmaceutically acceptable salt or ester thereof, or acompound of formulas 1-103 or a pharmaceutically acceptable salt orester thereof).

One embodiment provides a method of treating a Pneumovirinae infectionin a mammal (e.g., a human) in need thereof by administering atherapeutically effective amount of a tautomer, polymorph,pseudopolymorph, amorphous form, hydrate or solvate of a compounddisclosed herein or a pharmaceutically acceptable salt or ester thereof(e.g., a compound of formula I or a pharmaceutically acceptable salt orester thereof, or a compound of formulas 1-103 or a pharmaceuticallyacceptable salt or ester thereof).

One embodiment provides a method of treating a respiratory syncytialvirus infection in a mammal (e.g., a human) in need thereof byadministering a therapeutically effective amount of a compound disclosedherein or a pharmaceutically acceptable salt or ester thereof (e.g., acompound of formula I or a pharmaceutically acceptable salt or esterthereof, or a compound of formulas 1-103 or a pharmaceuticallyacceptable salt or ester thereof).

One embodiment provides a method of treating a respiratory syncytialvirus infection in a mammal (e.g., a human) in need thereof byadministering a therapeutically effective amount of a tautomer,polymorph, pseudopolymorph, amorphous form, hydrate or solvate of acompound disclosed herein or a pharmaceutically acceptable salt or esterthereof (e.g., a compound of formula I or a pharmaceutically acceptablesalt or ester thereof, or a compound of formulas 1-103 or apharmaceutically acceptable salt or ester thereof).

One embodiment provides a method of treating a Pneumovirinae infection(e.g., a respiratory syncytial virus infection) in a mammal (e.g., ahuman) in need thereof by administering a therapeutically effectiveamount of a compound disclosed herein or a pharmaceutically acceptablesalt or ester thereof (e.g., a compound of formula I or apharmaceutically acceptable salt or ester thereof, or a compound offormulas 1-103 or a pharmaceutically acceptable salt or ester thereof),and a pharmaceutically acceptable diluent or carrier.

One embodiment provides a method of treating a Pneumovirinae infection(e.g., a respiratory syncytial virus infection) in a mammal (e.g., ahuman) in need thereof by administering a therapeutically effectiveamount of a compound disclosed herein or a pharmaceutically acceptablesalt or ester thereof (e.g., a compound of formula I or apharmaceutically acceptable salt or ester thereof, or a compound offormulas 1-103 or a pharmaceutically acceptable salt or ester thereof),in combination with at least one additional therapeutic agent.

One embodiment provides a method of treating a Pneumovirinae infectionin a mammal (e.g., a human) in need thereof, by administering atherapeutically effective amount of a combination pharmaceutical agentcomprising:

a) a first pharmaceutical composition comprising a compound disclosedherein or a pharmaceutically acceptable salt or ester thereof (e.g., acompound a of formula I or a pharmaceutically acceptable salt or esterthereof, or a compound of formulas 1-103 or a pharmaceuticallyacceptable salt or ester thereof); and

b) a second pharmaceutical composition comprising at least oneadditional therapeutic agent active against infectious Pneumovirinaeviruses.

One embodiment provides a method of treating a Pneumovirinae infectionin a mammal (e.g., a human) in need thereof, by administering atherapeutically effective amount of a combination pharmaceutical agentcomprising:

a) a therapeutic agent selected from a compound disclosed herein or apharmaceutically acceptable salt or ester thereof (e.g., a compound a offormula I and pharmaceutically acceptable salts and esters thereof, anda compound of formulas 1-103 and pharmaceutically acceptable salts oresters thereof; and

b) a therapeutic agent active against infectious Pneumovirinae viruses.

One embodiment provides a method of treating a respiratory syncytialvirus infection in a mammal (e.g., a human) in need thereof, byadministering a therapeutically effective amount of a combinationpharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound disclosedherein or a pharmaceutically acceptable salt or ester thereof (e.g., acompound of formula I or a pharmaceutically acceptable salt or esterthereof, or a compound of formulas 1-103 or a pharmaceuticallyacceptable salt or ester thereof); and

b) a second pharmaceutical composition comprising at least oneadditional therapeutic agent active against infectious respiratorysyncytial viruses.

One embodiment provides a method of treating a respiratory syncytialvirus infection in a mammal (e.g., a human) in need thereof, byadministering a therapeutically effective amount of a combinationpharmaceutical agent comprising:

a) a therapeutic agent selected from a compound disclosed herein or apharmaceutically acceptable salt or ester thereof (e.g., a compound a offormula I and pharmaceutically acceptable salts and esters thereof and acompound of formulas 1-103 and pharmaceutically acceptable salts oresters thereof; and

b) a therapeutic agent active against infectious Pneumovirinae viruses.

One embodiment provides compound disclosed herein or a pharmaceuticallyacceptable salt or ester thereof (e.g., a compound of formula I or apharmaceutically acceptable salt or ester thereof, or a compound offormulas 1-103 or a pharmaceutically acceptable salt or ester thereof)for use in medical therapy.

One embodiment provides a compound disclosed herein or apharmaceutically acceptable salt or ester thereof (e.g., a compound offormula I or a pharmaceutically acceptable salt or ester thereof, or acompound of formulas 1-103 or a pharmaceutically acceptable salt orester thereof for use in the prophylactic or therapeutic treat a viralinfection caused by a Pneumovirinae virus or a respiratory syncytialvirus.

One embodiment provides the use of a compound disclosed herein or apharmaceutically acceptable salt or ester thereof (e.g., a compound offormula I or a pharmaceutically acceptable salt or ester thereof, or acompound of formulas 1-103 or a pharmaceutically acceptable salt orester thereof) for the manufacture of a medicament useful for thetreatment of a viral infection caused by a Pneumovirinae virus or arespiratory syncytial virus.

One embodiment provides processes and novel intermediates disclosedherein which are useful for preparing a compound disclosed herein (e.g.,a compound of formula I or a compound of formulas 1-103).

One embodiment provides novel methods for synthesis, analysis,separation, isolation, purification, characterization, and testing ofthe compounds disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

The term “alkyl” refers to a straight or branched hydrocarbon. Forexample, an alkyl group can have 1 to 20 carbon atoms (i.e, C₁-C₂₀alkyl), 1 to 8 carbon atoms (i.e., C₁-C₈ alkyl), or 1 to 6 carbon atoms(i.e., C₁-C₆ alkyl). Examples of suitable alkyl groups include, but arenot limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr,n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl(n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

The term “alkoxy” refers to a group having the formula —O-alkyl, inwhich an alkyl group, as defined above, is attached to the parentmolecule via an oxygen atom. The alkyl portion of an alkoxy group canhave 1 to 20 carbon atoms (i.e., C₁-C₂₀ alkoxy), 1 to 12 carbon atoms(i.e., C₁-C₁₂ alkoxy), or 1 to 6 carbon atoms (i.e., C₁-C₆ alkoxy).Examples of suitable alkoxy groups include, but are not limited to,methoxy (—O—CH₃ or —OMe), ethoxy (—OCH₂CH₃ or —OEt), t-butoxy(—O—C(CH₃)₃ or —OtBu) and the like.

The term “haloalkyl” refers to an alkyl group, as defined above, inwhich one or more hydrogen atoms of the alkyl group is replaced with ahalogen atom. The alkyl portion of a haloalkyl group can have 1 to 20carbon atoms (i.e., C₁-C₂₀ haloalkyl), 1 to 12 carbon atoms (i.e.,C₁-C₁₂ haloalkyl), or 1 to 6 carbon atoms (i.e., C₁-C₆ alkyl). Examplesof suitable haloalkyl groups include, but are not limited to, —CF₃,—CHF₂, —CFH₂, —CH₂CF₃, and the like.

The term “alkenyl” refers to a straight or branched hydrocarbon with atleast one site of unsaturation, i.e., a carbon-carbon, sp² double bond.For example, an alkenyl group can have 2 to 20 carbon atoms (i.e.,C₂-C₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂-C₈ alkenyl), or 2 to 6carbon atoms (i.e., C₂-C₆ alkenyl). Examples of suitable alkenyl groupsinclude, but are not limited to, ethylene or vinyl (—CH═CH₂), allyl(—CH₂CH═CH₂), cyclopentenyl (—C₅H₇), and 5-hexenyl(—CH₂CH₂CH₂CH₂CH═CH₂).

The term “alkynyl” refers to a straight or branched hydrocarbon with atleast one site of unsaturation, i.e., a carbon-carbon, sp triple bond.For example, an alkynyl group can have 2 to 20 carbon atoms (i.e.,C₂-C₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂-C₈ alkyne,), or 2 to 6carbon atoms (i.e., C₂-C₆ alkynyl). Examples of suitable alkynyl groupsinclude, but are not limited to, acetylenic (—C≡CH), propargyl(—CH₂C≡CH), and the like.

The term “halogen” or “halo” refers to F, Cl, Br, or I.

The term “aryl” refers to an aromatic hydrocarbon radical derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. For example, an aryl group can have 6 to 20 carbonatoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical arylgroups include, but are not limited to, radicals derived from benzene(e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl,and the like.

The term “arylalkyl” refers to an acyclic alkyl radical as describedherein in which one of the hydrogen atoms bonded to a carbon atom, isreplaced with an aryl radical as described herein. Typical arylalkylgroups include, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like.

The arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkylmoiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbonatoms.

The term “substituted” in reference to alkyl, alkylene, aryl, arylalkyl,alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., for example,“substituted alkyl”, “substituted alkylene”, “substituted aryl”,“substituted arylalkyl”, “substituted heterocyclyl”, and “substitutedcarbocyclyl”, unless otherwise indicated, means alkyl, alkylene, aryl,arylalkyl, heterocyclyl, carbocyclyl, respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to, —X,—R^(b), —O—, ═O, —OR^(b), —SR^(b), —S⁻, —NR^(b) ₂, —N⁺R^(b) ₃, ═NR^(b),—CX₃, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, —N₂, —N₃, —NHC(═O)R^(b),—OC(═O)R^(b), —NHC(═O)NR^(b) ₂, —S(═O)₂—, —S(═O)₂OH, —S(—O)₂R^(b),—OS(═O)₂OR^(b), —S(═O)₂NR^(b) ₂, —S(═O)R^(b), —OP(═O)(OR^(b))₂,—P(═O)(OR^(b))₂, —P(═O)(O⁻)₂, —P(═O)(OH)₂, —P(O)(OR^(b))(O⁻),—C(═O)R^(b), —C(═O)X, —C(S)R^(b), —C(O)OR^(b), —C(O)O⁻, —C(S)OR^(b),—C(O)SR^(b), —C(S)SR^(b), —C(O)NR^(b) ₂, —C(S)NR^(b) ₂,—C(═NR^(b))NR^(b) ₂, where each X is independently a halogen: F, Cl, Br,or I; and each R^(b) is independently H, alkyl, aryl, arylalkyl, aheterocycle, or a protecting group or prodrug moiety. Alkylene,alkenylene, and alkynylene groups may also be similarly substituted.Unless otherwise indicated, when the term “substituted” is used inconjunction with groups such as arylalkyl, which have two or moremoieties capable of substitution, the substituents can be attached tothe aryl moiety, the alkyl moiety, or both.

The term “heterocycle” or “heterocyclyl” as used herein includes by wayof example and not limitation those heterocycles described in Paquette,Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, NewYork, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistryof Heterocyclic Compounds. A Series of Monographs” (John Wiley & Sons,New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment ofthe invention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have beenreplaced with a heteroatom (e.g., O, N, or S). The terms “heterocycle”or “heterocyclyl” includes saturated rings, partially unsaturated rings,and aromatic rings (i.e., heteroaromatic rings). Substitutedheterocyclyls include, for example, heterocyclic rings substituted withany of the substituents disclosed herein including carbonyl groups. Anon-limiting example of a carbonyl substituted heterocyclyl is:

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or 3-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

The term “heterocyclyl” refers to a monocyclic heterocyclyl ring or apolycyclic heterocyclyl ring, wherein the monocyclic heterocyclyl ringor polycyclic heterocyclyl ring has between 2-20 carbon atoms in thering system and 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogenand sulfur in the ring system, which heterocyclyl is also referred to asa C₂-C₂₀ heterocyclyl. The C₂-C₂₀ heterocyclyl can be saturated,partially unsaturated or aromatic. The rings of a polycyclic C₂-C₂₀heterocyclyl can be connected to one another by fused, bridged or spirobonds.

The term “heteroaryl” refers to an aromatic heterocyclyl having at leastone heteroatom in the ring. Non-limiting examples of suitableheteroatoms which can be included in the aromatic ring include oxygen,sulfur, and nitrogen. Non-limiting examples of heteroaryl rings includeall of those aromatic rings listed in the definition of “heterocyclyl”,including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl,furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl,pyridazyl, pyrimidyl, pyrazyl, etc.

The term “heterocyclylalkyl” refers to an acyclic alkyl radical asdescribed herein in which one of the hydrogen atoms bonded to a carbonatom is replaced with a heterocyclyl radical as described herein. It isto be understood that the hetereocyclyl can be connected to the alkylgroup at any acceptable carbon or heteroatom of the hetereocyclyl.Typical, but non-limiting, examples of heterocyclylalkyl groups includepyridylmethyl, pyrimidinylethyl, piperidinylmethyl and1-imidazolylethyl.

The term “carbocycle” or “carbocyclyl” refers to a saturated (i.e.,cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl,etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to12 carbon atoms as a bicycle, and up to about 20 carbon atoms as apolycycle. Monocyclic carbocycles have 3 to 7 ring atoms, still moretypically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ringatoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system,or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, orspiro-fused rings. Non-limiting examples of monocyclic carbocyclesinclude cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, l-cyclohex-3-enyl, and phenyl. Non-limiting examplesof bicyclo carbocycles includes naphthyl, tetrahydronapthalene, anddecaline.

The term “cycloalkyl” refers to a saturated or partially unsaturatedring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms asa bicycle, and up to about 20 carbon atoms as a polycycle. Monocycliccycloalkyl groups have 3 to 7 ring atoms, still more typically 5 or 6ring atoms. Bicyclic cycloalkyl groups have 7 to 12 ring atoms, e.g.,arranged as a bicyclo (4,5), (5,5), (5,6) or (6,6) system, or 9 or 10ring atoms arranged as a bicyclo (5,6) or (6,6) system. Cycloalkylgroups include hydrocarbon mono-, bi-, and poly-cyclic rings, whetherfused, bridged, or spiro. Non-limiting examples of monocycliccarbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,bicyclo[3.1.0]hex-6-yl and the like.

The term “cycloalkylalkyl” refers to an acyclic alkyl radical asdescribed herein in which one of the hydrogen atoms bonded to a carbonatom is replaced with a cycloalkyl radical as described herein. Typical,but non-limiting, examples of carbocyclylalkyl groups includecyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyland cyclohexylmethyl.

The term “carbocyclylalkyl” refers to an acyclic alkyl radical asdescribed herein in which one of the hydrogen atoms bonded to a carbonatom is replaced with a carbocyclyl radical as described herein.Typical, but non-limiting, examples of carbocyclylalkyl groups includecyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyland cyclohexylmethyl.

The term “optionally substituted” in reference to a particular moiety ofthe compound of formula I (e.g., an optionally substituted aryl or alkylgroup) refers to a moiety wherein all substitutents are hydrogen orwherein one or more of the hydrogens of the moiety may be replaced bysubstituents such as those listed under the definition of“substituted”or as otherwise indicated.

Selected substituents comprising the compounds of formula I may bepresent to a recursive degree. In this context, “recursive substituent”means that a substituent may recite another instance of itself. Themultiple recitations may be direct or indirect through a sequence ofother substituents. Because of the recursive nature of suchsubstituents, theoretically, a large number of compounds may be presentin any given embodiment. One of ordinary skill in the art of medicinalchemistry understands that the total number of such substituents isreasonably limited by the desired properties of the compound intended.Such properties include, by way of example and not limitation, physicalproperties such as molecular weight, solubility or log P, applicationproperties such as activity against the intended target, and practicalproperties such as ease of synthesis. Recursive substituents may be anintended aspect of the invention. One of ordinary skill in the art ofmedicinal chemistry understands the versatility of such substituents. Tothe degree that recursive substituents are present in an embodiment ofthe invention, they may recite another instance of themselves, 0, 1, 2,3, or 4 times.

One skilled in the art will recognize that substituents and othermoieties of the compounds of formula I should be selected in order toprovide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of formula Iwhich have such stability are contemplated as falling within the scopeof the present invention.

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. The chemical substructure of a protecting group varieswidely. One function of a protecting group is to serve as anintermediate in the synthesis of the parental drug substance. Chemicalprotecting groups and strategies for protection/deprotection are wellknown in the art. See: “Protective Groups in Organic Chemistry”,Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protectinggroups are often utilized to mask the reactivity of certain functionalgroups, to assist in the efficiency of desired chemical reactions, e.g.making and breaking chemical bonds in an ordered and planned fashion.Protection of functional groups of a compound alters other physicalproperties besides the reactivity of the protected functional group,such as the polarity, lipophilicity (hydrophobicity), and otherproperties which can be measured by common analytical tools. Chemicallyprotected intermediates may themselves be biologically active orinactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g. alcohols, be physiologicallyacceptable, although in general it is more desirable if the products arepharmacologically innocuous.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.,active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically active compound.

“Prodrug moiety” means a labile functional group which separates fromthe active inhibitory compound during metabolism, systemically, inside acell, by hydrolysis, enzymatic cleavage, or by some other process(Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook ofDrug Design and Development (1991), P. Krogsgaard-Larsen and H.Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes whichare capable of an enzymatic activation mechanism with, for example anyphosphate or phosphonate prodrug compounds of the invention, include butare not limited to, amidases, esterases, microbial enzymes,phospholipases, cholinesterases, and phosphases. Prodrug moieties canserve to enhance solubility, absorption and lipophilicity to optimizedrug delivery, bioavailability and efficacy. A prodrug moiety mayinclude an active metabolite or drug itself.

It is to be noted that all tautomers, polymorphs, pseudopolymorphs ofcompounds within the scope of formula I and pharmaceutically acceptablesalts and esters thereof and compounds of formulas 1-103 andpharmaceutically acceptable salts and esters thereof are embraced by thepresent invention.

It is also to be noted that all stereoisomers (e.g., enantiomers,diastercomers, atropisomers etc.) of compounds within the scope offormula I and pharmaceutically acceptable salts and esters thereof andcompounds of formulas 1-103 and pharmaceutically acceptable salts andesters thereof are embraced by the present invention.

A compound of formula I or a compound of formulas 1-103, and theirpharmaceutically acceptable salts may exist as different polymorphs orpseudopolymorphs. As used herein, crystalline polymorphism means theability of a crystalline compound to exist in different crystalstructures. The crystalline polymorphism may result from differences incrystal packing (packing polymorphism) or differences in packing betweendifferent conformers of the same molecule (conformational polymorphism).As used herein, crystalline pseudopolymorphism means the ability of ahydrate or solvate of a compound to exist in different crystalstructures. The pseudopolymorphs of the instant invention may exist dueto differences in crystal packing (packing pseudopolymorphism) or due todifferences in packing between different conformers of the same molecule(conformational pseudopolymorphism). The instant invention comprises allpolymorphs and pseudopolymorphs of the compounds of formula I andformulas 1-103, and their pharmaceutically acceptable salts.

A compound of formula I or a compound of formulas 1-103 and theirpharmaceutically acceptable salts may also exist as an amorphous solid.As used herein, an amorphous solid is a solid in which there is nolong-range order of the positions of the atoms in the solid. Thisdefinition applies as well when the crystal size is two nanometers orless. Additives, including solvents, may be used to create the amorphousforms of the instant invention. The instant invention comprises allamorphous forms of the compounds of formula I and formulas 1-103 andtheir pharmaceutically acceptable salts.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity).

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, refers to the act of treating, as “treating” is definedimmediately above.

The term “therapeutically effective amount”, as used herein, is theamount of compound of formula I or a compound of formulas 1-103 presentin a composition described herein that is needed to provide a desiredlevel of drug in the secretions and tissues of the airways and lungs, oralternatively, in the bloodstream of a subject to be treated to give ananticipated physiological response or desired biological effect whensuch a composition is administered by the chosen route ofadministration. The precise amount will depend upon numerous factors,for example the particular compound of formula I or the compound offormulas 1-103, the specific activity of the composition, the deliverydevice employed, the physical characteristics of the composition, itsintended use, as well as patient considerations such as severity of thedisease state, patient cooperation, etc., and can readily be determinedby one skilled in the art and in reference to the information providedherein.

The term “normal saline” means a water solution containing 0.9% (w/v)NaCl.

The term “hypertonic saline” means a water solution containing greaterthan 0.9% (w/v) NaCl. For example, 3% hypertonic saline would contain 3%(w/v) NaCl.

Any reference to the compounds of the invention described herein alsoincludes a reference to a physiologically acceptable salt (e.g.,pharmaceutically acceptable salt) thereof. Examples of physiologicallyacceptable salts of the compounds of the invention include salts derivedfrom an appropriate base, such as an alkali metal or an alkaline earth(for example, Na⁺, Li⁺, K⁺, Ca⁺² and Mg⁺²), ammonium and NR₄ ⁺ (whereinR is defined herein). Physiologically acceptable salts of a nitrogenatom or an amino group include (a) acid addition salts formed withinorganic acids, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and thelike; (b) salts formed with organic acids such as, for example, aceticacid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaricacid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoicacid, isethionic acid, lactobionic acid, tannic acid, palmitic acid,alginic acid, polyglutamic acid, naphthalenesulfonic acid,methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,naphthalenedisulfonic acid, polygalacturonic acid, malonic acid,sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate,salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid,ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine,threonine, alanine, isoleucinc, lcucine and the like; and (c) saltsformed from elemental anions for example, chlorine, bromine, and iodine.Physiologically acceptable salts of a compound of a hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NR₄ ⁺. In one embodiment each R is independently H or(C₁-C₆)alkyl.

For therapeutic use, salts of active ingredients of the compounds of theinvention will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedfrom a physiologically acceptable acid or base, are within the scope ofthe present invention.

It is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l, D and L, or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with S, (−), or 1 meaning that the compound islevorotatory while a compound prefixed with R, (+), or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The compounds disclosed herein, exemplified by formula I and formulas1-103 may have chiral centers, e.g. chiral carbon. The compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers. Individualenantiomers or diasteromers, isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The stereoisomeric mixtures are separated intotheir individual, substantially optically pure isomers throughwell-known techniques such as, for example, the separation ofdiastereomeric salts formed with optically active adjuncts, e.g., acidsor bases followed by conversion back to the optically active substances.In most instances, the desired optical isomer is synthesized by means ofstereospecific reactions, beginning with the appropriate stereoisomer ofthe desired starting material.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography. Enantiomers” refer to twostereoisomers of a compound which are non-superimposable mirror imagesof one another.

It is to be understood that for compounds disclosed herein includingcompounds of the invention (e.g., compounds of formula I (compounds104-122) and compounds 1-103) when a bond is drawn in anon-stereochemical manner (e.g., flat) the atom to which the bond isattached includes all stereochemical possibilities. It is also tounderstood that when a bond is drawn in a stereochemical manner (e.g.,bold, bold-wedge, dashed or dashed-wedge) the atom to which thestereochemical bond is attached has the stereochemistry as shown unlessotherwise noted.

Accordingly, in one embodiment, the compounds of the invention aregreater than 50% a single enantiomer. In another embodiment, thecompounds of the invention are at least 51% a single enantiomer. Inanother embodiment, the compounds of the invention are at least 60% asingle enantiomer. In another embodiment, the compounds of the inventionare at least 70% a single enantiomer. In another embodiment, thecompounds of the invention are at least 80% a single enantiomer. Inanother embodiment, the compounds of the invention are at least 90% asingle enantiomer. In another embodiment, the compounds of the inventionare at least 95% a single enantiomer. In another embodiment, thecompounds of the invention are at least 98% a single enantiomer. Inanother embodiment, the compounds of the invention are at least 99% asingle enantiomer. In another embodiment, the compounds of the inventionare greater than 50% a single diasteromer. In another embodiment, thecompounds of the invention are at least 51% a single diasteromer. Inanother embodiment, the compounds of the invention are at least 60% asingle diastereomer. In another embodiment, the compounds of theinvention are at least 70% a single diastereomer. In another embodiment,the compounds of the invention are at least 80% a single diastereomer.In another embodiment, the compounds of the invention are at least 90% asingle diastereomer. In another embodiment, the compounds of theinvention are at least 95% a single diastereomer. In another embodiment,the compounds of the invention of are at least 98% a singlediastereomer. In another embodiment, the compounds of the invention areat least 99% a single diastereomer.

Certain compounds disclosed herein including compounds of the inventionare represented by formula Ic (and salts and esters, thereof) as shownbelow wherein a position of chirality is marked with an asterisk.

The chirality at the asterisk position is a feature of these certaincompounds of formula Ic (as well as compounds of related formulas). Thestereochemistry at the carbon marked with an asterisk as shown above forformula Ic is the (S) stereochemistry provided that A is ranked thelowest (3) or highest (1) of the three substituents of the asteriskcarbon following the Cahn-Ingold-Prelog system or the (R)stereochemistry provided that A is ranked number 2 of the threesubstituents of the asterisk carbon following the Cahn-Ingold-Prelogsystem (March, J., Advanced Organic Chemistery, 4^(th) Addition, JohnWiley and Sons, pages 109-111). For example, the stereochemistry at thecarbon marked with an asterisk as shown above for formula Ic wherein Ais for example, an alkyl group (e.g., —(CH₂)₃₋₆—), is the (S)stereochemistry. In one embodiment, the compounds of the invention offormula Ic are greater than 50% a single stereoisomer at the asteriskposition. In another embodiment, the compounds of the invention offormula Ic are at least 60% a single stereoisomer at the asteriskposition. In another embodiment, the compounds of the invention offormula Ic are at least 70% a single stereoisomer at the asteriskposition. In another embodiment, the compounds of the invention offormula Ic are at least 80% a single stereoisomer at the asteriskposition. In another embodiment, the compounds of the invention offormula Ic are at least 90% a single stereoisomer at the asteriskposition. In another embodiment, the compounds of the invention offormula Ic are at least 95% a single stereoisomer at the asteriskposition.

Certain compounds disclosed herein including compounds of the inventioncan be represented by formula II (and salts and esters, thereof) asshown below wherein a position of chirality is marked with an asterisk.This formula is representative of compounds 1-103 wherein the R, X andAr groups in formula II represent the corresponding groups of thecompounds 1-103.

The chirality at the asterisk position is a feature of these certaincompounds of the invention of formula II (as well as compounds ofrelated formulas). The stereochemistry at the carbon marked with anasterisk as shown above for formula II is the (S) stereochemistry. Inone embodiment, the compounds of the invention represented by formula IIare greater than 50% a single stereoisomer at the asterisk position. Inanother embodiment, the compounds of the invention represented byformula II are at least 60% a single stereoisomer at the asteriskposition. In another embodiment, the compounds of the inventionrepresented by formula II are at least 70% a single stereoisomer at theasterisk position. In another embodiment, the compounds of the inventionrepresented by formula II are at least 80% a single stereoisomer at theasterisk position. In another embodiment, the compounds of the inventionrepresented by formula II are at least 90% a single stereoisomer at theasterisk position. In another embodiment, the compounds of the inventionrepresented by formula II are at least 95% a single stereoisomer at theasterisk position.

Compounds disclosed herein including compounds of formula I and formulas1-103 also include molecules that incorporate isotopes of the atomsspecified in the particular molecules. Non-limiting examples of theseisotopes include D, T, ¹⁴C, ¹³C and ¹⁵N.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R” or “R¹”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines,

, indicate the site of covalent bond attachments to the adjoiningsubstructures, groups, moieties, or atoms.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one dclocalizcd resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdescription, structures and formulas. While the invention will bedescribed in conjunction with the embodiments, it will be understoodthat they are not intended to limit the invention to those embodiments.On the contraryl the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the fullscope of the present invention as described herein.

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents. Specificvalues listed are values for compounds of formula I as well as allrelated formulas (e.g., formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij,Ik, Im, In, Ip1, Ip2, Ip3, Ip4, Iq1, Iq2, Iq3, Iq4, Ir1, Ir2, Ir3, Ir4,Is1, Is2, Is3, Is4, It1, It2, It3, It4, Iu1, Iu2, Iu3, Iu4, Iv1, Iv2,Iv3, Iv4, Iw1, Iw2, Iw3, Iw4, Ix1, Ix2, Ix3 or Ix4)

A specific group of compounds of formula I are compounds of formula Ia:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Ib:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Ic:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Id:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Ie:

Another specific group of compounds of formula I are compounds offormula If:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Ig:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Ih:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Ii:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Ij:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Ik:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula Im:

and salts and esters, thereof.

Another specific group of compounds of formula I are compounds offormula In:

and salts and esters, thereof.

Additional specific groups of compounds of formula I are compounds offormula Ip1, Ip2, Ip3 or Ip4:

or a salt or ester, thereof.

Additional specific groups of compounds of formula I are compounds offormula Iq1, Iq2, Iq3 or Iq4:

or a salt or ester, thereof.

Additional specific groups of compounds of formula I are compounds offormula Ir1, Ir2, Ir3 or Ir4:

or a salt or ester, thereof.

Additional specific groups of compounds of formula I are compounds offormula Is1, Is2, Is3 or Is4:

or a salt or ester, thereof.

Additional specific groups of compounds of formula I are compounds offormula It1, It2, It3 or It4:

or a salt or ester, thereof.

Additional specific groups of compounds of formula I are compounds offormula Iu1, Iu2, Iu3 or Iu4:

or a salt or ester, thereof.

Additional specific groups of compounds of formula I are compounds offormula Iv1, Iv2, Iv3 or Iv4:

or a salt or ester, thereof.

Additional specific groups of compounds of formula I are compounds offormula Iw1, Iw2, Iw3 or Iw4:

or a salt or ester, thereof.

Additional specific groups of compounds of formula I are compounds offormula Ix1, Ix2, Ix3 or Ix4:

wherein Z is:

or a salt or ester, thereof.

A specific group of compounds of formula I are compounds wherein each R³and each R^(3′) is H.

A specific value for R³ is H.

A specific value for R^(3′) is H.

A specific value for n is 3.

A specific group of compounds of formula I are compounds wherein each pis 2.

A specific group of compounds of formula I are compounds wherein each R⁴and each R^(4′) is H.

A specific value for R⁴ is H.

A specific value for R^(4′) is H.

A specific value for A is —(CH₂)₃—.

A specific group of compounds of formula I are compounds wherein:

-   -   a) Y¹ is N, NH or CH, Y² is C, Y³ is N or CR^(8′), Y⁴ is N or C,        and Y⁵ is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³,        Y⁴ and Y⁵ are independently N, NH or NR^(2′); or    -   b) Y¹ is N, NH or CH, Y² is N or C, Y³ is CR^(8′), Y⁴ is N or C,        and Y⁵ is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³,        Y⁴ and Y⁵ are independently N, NH or NR^(2′).

Another specific group of compounds of formula I are compounds wherein:

-   -   a) Y¹ is N, Y² is C, Y³ is N, Y⁴ is N and Y⁵ is CR²; or    -   b) Y¹ is CH, Y² is C, Y³ is N, Y⁴ is N and Y⁵ is CR²; or    -   c) Y¹ is N, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y¹ is N; or    -   d) Y¹ is N, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y⁵ is CR²; or    -   e) Y¹ is N, Y² is N, Y³ is N, Y⁴ is C and Y⁵ is N; or    -   f) Y¹ is CH, Y² is N, Y³ is N, Y⁴ is C and Ysis N; or    -   g) Y¹ is N, Y² is C, Y³ is N, Y⁴ is C and Y⁵ is NR^(2′); or    -   h) Y¹ is CH, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y⁵ is N; or    -   i) Y¹ is NH, Y² is C, Y³ is N, Y⁴ is C and Y⁵ is CR².

Another specific group of compounds of formula I are compounds wherein:

-   -   a) Y¹ is N or CH, Y² is C, Y³ is N, Y⁴ is N and Y⁵ is CR²; or    -   b) Y¹ is N, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y⁵ is N or CR²;        or    -   c) Y¹ is N or CH, Y² is N, Y³ is N, Y⁴ is C and Y⁵ is N; or    -   d) Y¹ is N, Y² is C, Y³ is N, Y⁴ is C and Y⁵ is NR^(2′); or    -   e) Y¹ is CH, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y⁵ is N; or    -   f) Y¹ is NH, Y² is C, Y³ is N, Y⁴ is C and Y⁵ is CR².

Another specific group of compounds of formula I are compounds wherein:

-   -   a) Y¹ is N, Y² is C, Y³ is N, Y⁴ is N and Y⁵ is CR²; or    -   b) Y¹ is N, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y⁵ is CR².

Another specific group of compounds of formula I are compounds wherein:

-   -   a) Y¹ is N, NH or CH, Y² is C, Y³ is N, Y⁴ is N or C and Y⁵ is        NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵        are independently N, NH or NR^(2′); or    -   b) Y¹ is N, NH or CH, Y² is N or C, Y³ is N or CR^(8′), Y⁴ is N        or C and Y⁵ is N, wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵        are independently N or NH; or    -   c) Y¹ is N, NH or CH, Y² is N or C, Y³ is CR^(8′), Y⁴ is N or C        and Y⁵ is NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴        and Y⁵ are independently N, NH or NR^(2′).

It is to be understood that the values for Y¹, Y², Y³, Y⁴ and Y⁵ areeach selected so that the ring formed by Y¹, Y², Y⁴, Y⁵ and the carbonatom connected to Y¹ and Y⁵ is an aromatic ring.

It is to be understood that the values for Y¹, Y², Y³, Y⁴ and Y⁵ areeach selected so that the ring formed by Y¹, Y², Y⁴, Y⁵ and the carbonatom connected to Y¹ and Y⁵ is an aromatic ring, and the dashed bonds(----) are selected from single bonds and double bonds so that the ringformed by Y¹, Y², Y⁴, Y⁵ along with the carbon atom connected to Y¹ andY⁵ is an aromatic ring.

A specific value for Y¹ is N.

A specific value for Y⁵ is CR².

A specific value for R² is H.

A specific value for R^(2′) is H.

A specific value for R^(8′) is H.

A specific group of compounds of formula I are compounds wherein R^(2′),R² and R^(8′) are each H.

A specific value for R⁷ is H or (C₁-C₈)alkyl, wherein (C₁-C₈)alkyl isoptionally substituted with one or more oxo, halogen, hydroxy, NH₂, CN,N₃, N(R^(a))₂, NHR^(a), SH, SR^(a), S(O)_(p)R^(a), OR^(a), (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR¹¹, —C(═O)OH,—C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR^(a)S(O)_(p)N(R^(a))₂,—NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR_(a), —NHS(O)_(p)N(R^(a))₂,—NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).

Another specific value for R⁷ is H or (C₁-C₈)alkyl.

Another specific value for R⁷ is H or (C₁-C₂)alkyl.

Another specific value for R⁷ is H or methyl.

A specific value for R¹ is H, —NR¹¹R¹², (C₁-C₈)alkyl or C₂-C₂₀heterocyclyl, wherein (C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl is optionallysubstituted with one or more oxo, halogen, hydroxy, —NH₂, CN, N₃,—N(R^(a))₂, —NHR^(a), —SH, —SR^(a), —S(O)_(p)R^(a), —OR^(a),(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R, —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR_(a)S(O)_(p)N(R^(a))₂,—NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR^(a), —NHS(O)_(p)N(R^(a)),—NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).

Another specific value for R¹ is H, —NR¹¹R¹², (C₁-C₈)alkyl or C₂-C₂₀heterocyclyl.

Another specific value for R¹ is H, (C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl.

Another specific value for R¹ is H, —NR¹¹R¹² or (C₁-C₈)alkyl.

Another specific value for R¹ is H, (C₁-C₃)alkyl or —NR¹¹R¹², whereineach R¹¹ or R¹² is independently H or (C₁-C₃)alkyl; or R¹¹ and R¹²together with the nitrogen to which they are both attached to form a 3to 7 membered heterocyclic ring wherein any one carbon atom of saidheterocyclic ring can optionally be replaced with —O—, —S—, —S(O)_(p)—,—NH—, —NR^(a)- or —C(O)—.

Another specific value for R¹ is H, (C₁-C₃)alkyl or —NR¹¹R¹², whereineach R¹¹ or R¹² is independently H or (C₁-C₃)alkyl; or R¹¹ and R¹²together with the nitrogen to which they are both attached to form a 4to 5 membered heterocyclic ring.

Another specific value for R¹ is H, methyl or azetidinyl.

Another specific value for R¹ is H, (C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl,wherein C₂-C₂₀ heterocyclyl is optionally substituted with one or moreoxo, halogen, hydroxy, —NH₂, CN, N₃, —N(R^(a))₂, —NHR^(a), —SH, SR^(a),—S(O)_(p)R^(a), —OR^(a), (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a),—C(O)H, —C(═O)OR^(a), —C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a),—C(═O)NH₂, —NHS(O)_(p)R^(a), —NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a),—NR^(a)C(O)R^(a), —NHC(O)OR^(a), —NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a),—NR^(a)C(O)N(R^(a))₂, —NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂,—NHC(O)NH₂, ═NH, ═NOH, ═NOR^(a), —NR^(a)S(O)_(p)NHR^(a),—NR^(a)S(O)_(p)N(R^(a))₂, —NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR^(a),—NHS(O)_(p)N(R^(a))₂, —NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ orR^(a).

Another specific value for R¹ is H, (C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl.

Another specific value for R¹ is H, (C₁-C₈)alkyl or 3-7 memberedmonocyclic saturated heterocyclyl.

Another specific value for R¹ is H, (C₁-C₈)alkyl or 3-7 memberedmonocyclic saturated heterocyclyl wherein the 3-7 membered monocyclicsaturated heterocyclyl includes 2-6 carbon atoms in the ring and 1-3heteroatoms selected from oxygen, sulfur and nitrogen in the ring.

Another specific value for R¹ is H, (C₁-C₃)alkyl or 3-7 memberedmonocyclic saturated heterocyclyl wherein the 3-7 membered monocyclicsaturated heterocyclyl includes 2-6 carbon atoms in the ring and 1-3heteroatoms selected from oxygen, sulfur and nitrogen in the ring.

Another specific value for R¹ is H, (C₁-C₃)alkyl or 4-5 memberedmonocyclic saturated heterocyclyl wherein the 4-5 membered monocyclicsaturated heterocyclyl includes 3-4 carbon atoms in the ring and 1hetereoatom selected from oxygen, sulfur and nitrogen in the ring.

A specific value for R⁸ is NR¹¹R¹², (C₁-C₈)alkyl or C₂-C₂₀ heterocyclylwherein (C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl is optionally substitutedwith one or more oxo, halogen, hydroxy, —NH₂, CN, N₃, —N(R^(a))₂,—NHR^(a), —SH, —SR^(a), —S(O)_(p)R^(a), —OR^(a), (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a), —C(═O)OH,—C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR^(a)S(O)_(p)N(R^(a))₂, —NR^(a)S(O)pNH₂, —NHS(O)_(p)NHR^(a), —NHS(O)_(p)N(R^(a))₂, —NHS(O)_(p)NH₂,—OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).

Another specific value for R⁸ is (C₁-C₈)alkyl or 3-7 membered monocyclicsaturated heterocyclyl wherein (C₁-C₈)alkyl or 3-7 membered monocyclicsaturated heterocyclyl is optionally substituted with one or more oxo,halogen, hydroxy, —NH₂, CN, N₃, —N(R^(a))₂, —NHR^(a), —SH, —SR^(a),—S(O)_(p)R^(a), —OR^(a), (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a),—C(O)H, —C(═O)OR^(a), —C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a),—C(═O)NH₂, —NHS(O)_(p)R^(a), —NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a),—NR^(a)C(O)R^(a), —NHC(O)OR^(a), —NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a),—NR^(a)C(O)N(R^(a))₂, —NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂,—NHC(O)NH₂, ═NH, ═NOH, ═NOR^(a), —NR^(a)S(O)_(p)NHR^(a),—NR^(a)S(O)_(p)N(R^(a))₂, —NR^(a)S(O)_(p)NH₂, —NHS(O) pNHR^(a),—NHS(O)_(p)N(R^(a))₂, —NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ orR^(a).

Another specific value for R⁸ is (C₁-C₈)alkyl or 3-7 membered monocyclicsaturated heterocyclyl, wherein the 3-7 membered monocyclic saturatedheterocyclyl includes 2-6 carbon atoms in the ring and 1-3 heteroatomsselected from oxygen, sulfur and nitrogen in the ring, and wherein(C₁-C₈)alkyl or 3-7 membered monocyclic saturated heterocyclyl isoptionally substituted with one or more oxo, halogen, hydroxy, —NH₂, CN,N₃, —N(R^(a))₂, —NHR^(a), —SH, —SR^(a), —S(O)_(p)R^(a), —OR^(a),(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR^(a)S(O)_(p)N(R^(a))₂,—NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR^(a), —NHS(O)_(p)N(R^(a))₂,—NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).

Another specific value for R⁸ is (C₁-C₈)alkyl or 3-7 membered monocyclicsaturated heterocyclyl, wherein the 3-7 membered monocyclic saturatedheterocyclyl is optionally substituted with one or more hydroxy, NH₂ orCN.

Another specific value for R⁸ is (C₁-C₈)alkyl or 3-7 membered monocyclicsaturated heterocyclyl, wherein the 3-7 membered monocyclic saturatedheterocyclyl includes 2-6 carbon atoms in the ring and 1-3 heteroatomsselected from oxygen, sulfur and nitrogen in the ring, and wherein the3-7 membered monocyclic saturated heterocyclyl is optionally substitutedwith one or more hydroxy, NH₂ or CN.

Another specific value for R⁸ is (C₁-C₃)alkyl or 3-7 membered monocyclicsaturated heterocyclyl wherein 3-7 membered monocyclic saturatedheterocyclyl is optionally substituted with one or more hydroxy, NH₂ orCN.

Another specific value for R⁸ is (C₁-C₃)alkyl or 3-7 membered monocyclicsaturated heterocyclyl, wherein the 3-7 membered monocyclic saturatedheterocyclyl includes 2-6 carbon atoms in the ring and 1-3 heteroatomsselected from oxygen, sulfur and nitrogen in the ring, and wherein 3-7membered monocyclic saturated heterocyclyl is optionally substitutedwith one or more hydroxy, NH₂ or CN.

Another specific value for R⁸ is (C₁-C₂)alkyl or 4-5 membered monocyclicsaturated heterocyclyl, wherein the 4-5 membered monocyclic saturatedheterocyclyl includes 3-4 carbon atoms in the ring and one nitrogen atomin the ring, and wherein the 4-5 membered monocyclic saturatedheterocyclyl is optionally substituted with one or more hydroxy, NH₂ orCN.

Another specific value for R⁸ is (C₁-C₈)alkyl, azetidinyl orpyrrolidinyl, wherein azetidinyl or pyrrolidinyl is optionallysubstituted with one or more oxo, halogen, hydroxy, —NH₂, CN, N₃,—N(R^(a))₂, —NHR^(a), —SH, —SR^(a), —S(O)_(p)R^(a), —OR^(a),(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR^(a)S(O)_(p)N(R^(a))₂,—NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR^(a), —NHS(O)_(p)N(R^(a))₂,—NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).

Another specific value for R⁸ is methyl, azetidinyl or pyrrolidinyl,wherein azetidinyl or pyrrolidinyl is optionally substituted with one ormore hydroxy, NH₂ or CN.

A specific group of compounds of formula I are compounds wherein eachR^(a) is (C₁-C₈)alkyl.

A specific group of compounds of formula I are compounds wherein eachR^(a) is (C₁-C₃)alkyl.

A specific group of compounds of formula I are compounds wherein eachR^(a) is (C₁-C₂)alkyl.

A specific group of compounds of formula I are compounds wherein eachR^(a) is methyl.

A specific group of compounds of formula I are compounds wherein X is—C(R¹³)(R¹⁴)— or X is absent.

A specific value for R¹³ is H.

A specific value for R¹⁴ is —NR¹¹—S(O)_(p)R^(a).

A specific value for R¹⁴ is —NHS(O)₂(C₁-C₃)alkyl.

A specific value for R¹⁴ is —NHS(O)₂CH₃.

A specific group of compounds of formula I are compounds R¹³ is H andR¹⁴ is —NR¹¹S(O)_(p)R^(a).

A specific group of compounds of formula I are compounds R¹³ is H andR¹⁴ is —NHS(O)₂(C₁-C₃)alkyl.

A specific group of compounds of formula I are compounds wherein R¹³ isH and R¹⁴ is —NHS(O)₂CH₃.

A specific group of compounds of formula I are compounds wherein X is—C(H)(NHS(O)₂CH₃)— or X is absent.

A specific group of compounds of formula I are compounds wherein X isabsent.

A specific value for Ar is a phenyl or a pyridyl wherein the phenyl orpyridyl is optionally substituted with 1 to 5 R⁶.

Another specific value for Ar is a phenyl or 5-6 membered monocyclicheteroaryl, wherein phenyl or 5-6 membered monocyclic heteroaryl isoptionally substituted with 1 to 5 R⁶.

Another specific value for Ar is a phenyl, pyridinyl or thienyl, whereinphenyl, pyridinyl or thienyl is optionally substituted with 1 to 5 R⁶.

Another specific value for R⁶ is —NR¹¹S(O)_(p)R^(a), halogen,(C₁-C₈)alkyl or NR¹¹C(O)R¹¹.

Another specific value for R⁶ is —NR¹¹S(O)_(p)R^(a), halogen or(C₁-C₈)alkyl.

Another specific value for R⁶ is —NHS(O)₂(C₁-C₃)alkyl, halogen or(C₁-C₃)alkyl.

Another specific value for R⁶ is —NHS(O)₂CH₃, chloro, bromo or methyl.

A specific group of compounds of formula I are compounds wherein:

a) Y¹ is N, Y² is C, Y³ is N, Y⁴ is N and Y⁵ is CR²; or

b) Y¹ is CH, Y² is C, Y³ is N, Y⁴ is N and Y⁵ is CR²; or

c) Y¹ is N, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y⁵ is N; or

d) Y¹ is N, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y⁵ is CR²; or

e) Y¹ is N, Y² is N, Y¹ is N, Y⁴ is C and Y⁵ is N; or

e) Y¹ is CH, Y² is N, Y³ is N, Y⁴ is C and Y⁵ is N; or

g) Y¹ is N, Y² is C, Y³ is N, Y⁴ is C and Y⁵ is NR^(2′); or

h) Y¹ is CH, Y² is N, Y³ is CR^(8′), Y⁴ is C and Y⁵ is N; or

i) Y¹ is NH, Y² is C, Y³ is N, Y⁴ is C and Y⁵ is CR².

the dashed bonds ---- are selected from single bonds and double bonds soas to provide an aromatic ring system;

A is —(CR⁴R^(4′))—;

n is 3;

each p is 2;

Ar is a C₂-C₂₀ heterocyclyl group or a C₆-C₂₀ aryl group, wherein theC₂-C₂₀ heterocyclyl group or the C₆-C₂₀ aryl group is optionallysubstituted with 1 to 5 R⁶;

X is —C(R¹³)(R¹⁴)—, or X is absent;

R¹ is H, —NR¹¹R¹², (C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl;

R² is H;

R^(2′) is H;

R³ is H;

R^(3′) is H;

each R⁴ is H;

each R^(4′) is H;

each R⁶ is independently —NR¹¹S(O)_(p)R¹¹, halogen or (C₁-C₈)alkyl;

R⁷ is H or (C₁-C₈)alkyl;

R⁸ is (C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl;

R^(8′) is H;

each R^(a) is independently (C₁-C₈)alkyl;

each R¹¹ or R¹² is independently H; or when R¹¹ and R¹² are attached toa nitrogen they may optionally be taken together with the nitrogen towhich they are both attached to form a 3 to 7 membered heterocyclic ringwherein any one carbon atom of said heterocyclic ring can optionally bereplaced with —O—, —S—, —S(O)_(p)—, —NH—, —NR^(a)- or —C(O)—;

R¹³ is H;

R¹⁴ is NR¹¹S(O)_(p)R^(a); and

wherein each C₂-C₂₀ heterocyclyl of each R¹ or R⁸ is independently,optionally substituted with one or more hydroxy, —NH₂ or CN.

In one embodiment the compounds of formula I do not include compoundswherein Y³ is N and R¹ is OH.

A specific group of compounds of formula I and salts and esters, thereofare compounds wherein:

a) Y¹ is N, NH or CH, Y² is C, Y³ is N or CR^(8′), Y⁴ is N or C and Y⁵is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently N, NH or NR^(2′); or

b) Y¹ is N, NH or CH, Y² is N or C, Y³ is N or CR^(8′), Y⁴ is N or C andY⁵ is N or NR^(2′), wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently N, NH or NR^(2′); or

c) Y¹ is N, NH or CH, Y² is N or C, Y³ is CR^(8′), Y⁴ is N or C and Y⁵is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently N, NH or NR^(2′);

the dashed bonds ---- are selected from single bonds and double bonds soas to provide an aromatic ring system;

A is —(CR⁴ R^(4′))_(n)— wherein any one CR⁴ R^(4′) of said —(CR⁴R^(4′))_(n)— may be optionally replaced with —O—, —S—, —S(O)_(p)—, NH orNR^(a);

n is 3, 4, 5 or 6;

each p is 1 or 2;

Ar is a C₂-C₂₀ heterocyclyl group or a C₆-C₂₀ aryl group, wherein theC₂-C₂₀ heterocyclyl group or the C₆-C₂₀ aryl group is optionallysubstituted with 1 to 5 R⁶;

X is —C(R¹³)(R¹⁴)—, —N(CH₂R¹⁴)—, —NH— or X is absent;

R¹ is H, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, —SR¹¹, —S(O)_(p)R¹¹, —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R² is H, CN, NO₂, halogen or (C₁-C₈)alkyl;

R^(2′) is H or (C₁-C₈)alkyl;

R³ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃,CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R^(3′) is H, OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R⁴ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃,CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R^(4′) is H, OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R⁵ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃,CN, NO₂, S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹),—NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R^(5′) is H, OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

each R⁶ is independently H, oxo, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹,NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, SR¹¹, S(O)_(p)R^(a),NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —YNR¹¹SO_(p)NR¹¹R¹²,NR¹¹C(═NR₁₁)NR¹¹R¹², halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R⁷ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃,CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R⁸ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃,CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R^(8′) is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₅)alkyl;

-   -   each R^(a) is independently (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl,        C₂-C₂₀ heterocyclyl, (C₃-C₇)cycloalkyl or        (C₃-C₇)cycloalkyl(C₁-C₈)alkyl wherein any (C₁-C₈)alkyl,        (C₁-C₈)haloalkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of R^(a) is        optionally substituted with one or more OH, NH₂, CO₂H, C₂-C₂₀        heterocyclyl, and wherein any aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl,        C₂-C₂₀ heterocyclyl, (C₃-C₇)cycloalkyl or        (C₃-C₇)cycloalkyl(C₁-C₈)alkyl of R^(a) is optionally substituted        with one or more (e.g., 1, 2 3, 4 or 5) OH, NH₂, CO₂H, C₂-C₂₀        heterocyclyl or (C₁-C₈)alkyl;    -   each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl,        (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl,        C₂-C₂₀ heterocyclyl, (C₃-C₇)cycloalkyl,        (C₃-C₇)cycloalkyl(C₁-C₈)alkyl, —C(═O)R^(a) or —S(O)_(p)R^(a); or        R¹¹ and R¹² taken together with a nitrogen to which they are        both attached form a 3 to 7 membered heterocyclic ring wherein        any one carbon atom of said heterocyclic ring can optionally be        replaced with —O—, —S—, —S(O)_(p)—, —NH—, —NR^(a)- or —C(O)—;

R¹³ is H or (C₁-C₈)alkyl;

R¹⁴ is H, (C₁-C₈)alkyl, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,NR¹¹C(O)NR¹¹R¹², NR¹¹S(O)_(p)R^(a), —NR¹¹S(O)_(p)(OR¹¹) orNR¹¹SO_(p)NR¹¹R¹²; and wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl of each R¹, R²,R^(2′), R³, R^(3′), R⁴, R^(4′), R⁵, R^(5′), R⁶, R⁷, R⁸, R^(8′), R¹¹ orR¹² is independently, optionally substituted with one or more (e.g., 1,2 3, 4, 5 or more) oxo, halogen, hydroxy, NH₂, CN, N₃, N(R^(a))₂,NHR^(a), SH, SR^(a), S(O)_(p)R^(a), OR^(a),(C₁-C₈)alkyl(C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR_(a), —C(═O)NH₂, NHS(O)_(p)R^(a),NR^(a)S(O)_(p)R^(a), NHC(O)R^(a), NR^(a)C(O)R¹¹, NHC(O)OR,NR^(a)C(O)OR^(a), NR^(a)C(O)NHR^(a), NR^(a)C(O)N(R^(a))₂, NR^(a)C(O)NH₂,NHC(O)NHR^(a), NHC(O)N(R^(a))₂, NHC(O)NH₂, ═NH, ═NOH, ═NOR^(a),NR^(a)S(O)_(p)NHR^(a), NR^(a)S(O)_(p)N(R^(a))₂, NR^(a)S(O)_(p)NH₂,NHS(O)_(p)NHR^(a), NHS(O)_(p)N(R^(a))₂, NHS(O)_(p)NH₂, —OC(═O)R^(a),—OP(O)(OH)₂ or R^(a).

In one embodiment the compounds of formula I are selected from compoundscompound of formula I, or a salt or ester, thereof; wherein:

a) Y¹ is N, NH or CH, Y² is C, Y³ is N or CR^(8′), Y⁴ is N or C and Y⁵is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently N, NH or NR^(2′); or

b) Y¹ is N, NH or CH; Y² is N or C; Y³ is N or CR^(8′), Y⁴ is N or C;and Y⁵ is N or NR^(2′), wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵are independently N, NH or NR^(2′); or

c) Y¹ is N, NH or CH; Y² is N or C; Y³ is CR^(8′); Y⁴ is N or C; and Y⁵is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently N, NH or NR^(2′);

the dashed bonds ---- are selected from single bonds and double bonds soas to provide an aromatic ring system;

A is —(CR⁴ R^(4′))_(n)— wherein any one CR⁴ R^(4′) of said—(CR⁴R^(4′))_(n)— may be optionally replaced with —O—, —S—, —S(O)_(p)—,NH or NR^(a);

n is 3, 4, 5 or 6;

each p is 1 or 2;

Ar is a C₂-C₂₀ heterocyclyl group or a C₆-C₂₀ aryl group, wherein theC₂-C₂₀ heterocyclyl group or the C₆-C₂₀ aryl group is optionallysubstituted with 1 to 5 R⁶;

X is —C(R¹³)(R¹⁴)—, —N(CH₂R¹⁴)— or —NH—, or X is absent (e.g., Ar isdirectly attached to the carbonyl of formula I);

R¹ is H, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, —SR¹¹, —S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ hctcrocycl (C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R² is H, CN, NO₂, halogen or (C₁-C₈)alkyl;

R^(2′) is H or (C₁-C₈)alkyl;

R³ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃,CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R^(3′) is H, OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

each R⁴ is independently H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹),—SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹²,NR¹¹C(═NR¹¹)NR¹¹R¹², halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

each R^(4′) is independently H, OR¹¹ (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

or two R⁴ on adjacent carbon atoms, when taken together, may form adouble bond between the two carbons to which they are attached or mayform a (C₃-C₇)cycloalkyl ring wherein one carbon atom of said(C₃-C₇)cycloalkyl ring may be optionally replaced by —O—, —S—,—S(O)_(p)—, —NH— or —NR^(a)—;

or two R⁴ on non-adjacent carbon atoms, when taken together, may form a(C₃-C₇)cycloalkyl ring wherein one carbon atom of said (C₃-C₇)cycloalkylring may be optionally replaced by —O—, —S—, —S(O)_(p)—, —NH— or—NR^(a)—;

or two R⁴ and two R^(4′) on adjacent carbon atoms, when taken together,may form an optionally substituted C₆ aryl ring;

or one R⁴ and one R^(4′) on the same carbon atom, when taken together,may form a (C₃-C₇)cycloalkyl ring wherein one carbon atom of said(C₃-C₇)cycloalkyl ring may be optionally replaced by —O—, —S—,—S(O)_(p)—, —NH— or —NR^(a)—;

each R⁵ is independently H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, SR¹¹, S(O)R^(a), NR¹¹S(O)_(p)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹),—SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹²,NR¹¹C(═NR¹¹)NR¹¹R¹², halogen (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ hctcrocycly (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

each R⁵ is independently H, OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

each R⁶ is independently H, oxo, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹,NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, SR¹¹, S(O)_(p)R^(a),NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹²,NR¹¹C(═NR¹¹)NR¹¹R¹², halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

or two R⁶ on adjacent carbon atoms, when taken together, may form a(C₃-C₇)cycloalkyl ring wherein one carbon atom of said (C₃-C₇)cycloalkylring may be optionally replaced by —O—, —S—, —S(O)_(p)—, —NH— or—NR^(a)—;

or any R⁶ adjacent to the obligate carbonyl group of said Ar, when takentogether with R³, may form a bond or a —(CR⁵R^(5′))_(m)— group wherein mis 1 or 2;

or any R⁶ adjacent to the obligate carbonyl group of said Ar, when takentogether with R² or R^(2′) may form a bond;

R⁷ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹², N₃,CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R⁸ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(ONR¹¹R¹², N₃,CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═ONR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

R^(8′) is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, SR¹¹, S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl;

each R^(a) is independently (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl wherein any (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of R^(a) isoptionally substituted with one or more OH, NH₂, CO₂H, C₂-C₂₀heterocyclyl, and wherein any aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀heterocyclyl, (C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl ofR^(a) is optionally substituted with one or more (e.g., 1, 2 3, 4 or 5)OH, NH₂, CO₂H, C₂-C₂₀ heterocyclyl or (C₁-C₈)alkyl;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₈)alkyl, —C(═O)R¹¹ or—S(O)_(p)R¹¹; or when R¹¹ and R¹² are attached to a nitrogen they mayoptionally be taken together with the nitrogen to which they are bothattached to form a 3 to 7 membered heterocyclic ring wherein any onecarbon atom of said heterocyclic ring can optionally be replaced with—O—, —S—, —S(O)_(p)—, —NH—, —NR^(a)- or —C(O)—;

R¹³ is H or (C₁-C₈)alkyl;

R¹⁴ is H, (C₁-C₈)alkyl, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,NR¹¹C(ONR¹¹R¹², NR¹¹S(O)_(p)R^(a), —NR¹¹S(O)_(p)(OR¹¹) orNR¹¹SO_(p)NR¹¹R¹²; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl of each R¹, R², R^(2′), R³, R^(3′), R⁴,R^(4′), R⁵, R^(5′), R⁶, R⁷, R⁸, R^(8′), R¹¹ or R¹² is independently,optionally substituted with one or more (e.g., 1, 2 3, 4, 5 or more)oxo, halogen, hydroxy, NH₂, CN, N₃, N(R^(a))₂, NHR^(a), SH, SR^(a),S(O)_(p)R^(a), OR^(a), (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a),—C(O)H, —C(═O)OR^(a), —C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a),—C(═O)NH₂, NHS(O)_(p)R^(a), NR^(a)S(O)_(p)R^(a), NHC(O)R^(a),NR^(a)C(O)R^(a), NHC(O)OR^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NHR^(a),NR^(a)C(O)N(R^(a))₂, NR^(a)C(O)NH₂, NHC(O)NHR^(a), NHC(O)N(R^(a))₂,NHC(O)NH₂, ═NH, ═NOH, ═NOR^(a), NR^(a)S(O)NHR^(a),NR^(a)S(O)_(p)N(R^(a))₂, NR^(a)S(O) pNH₂, NHS(O)_(p)NHR^(a),NHS(O)_(p)N(R^(a))₂, NHS(O) pNH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R.

In one embodiment a compound of formula I is selected from: 23.

and salts and esters, thereof.

In one embodiment a compound of the invention is selected from:

and salts and esters, thereof.

Esters of Compounds of the Invention

The compounds of the invention also include “esters” of the compounds ofthe invention. Accordingly, one example of esters of the compounds ofthe invention include esters wherein a hydroxyl group of the compound ofthe invention is an ester. These esters of the invention are typicallylabile and thus the ester may be converted to the corresponding hydroxylgroup in vivo (e.g., after administration). Esters include those estersbased on carbon and phosphorus.

Typical esters include: (R^(a)O)₂P(═O)O—,(HO)₂P(═O)O—(C₁-C₈)alkyl(C═O)O—, C₆-C₂₀aryl(C═O)O—,C₂-C₂₀heterocycyl(C═O)O— or (C₃-C₇)cyclolalkyl(C═O)O— wherein each(C₁-C₈)alkyl(C═O)O—, C₆-C₂₀aryl(C═O)O—, C₂-C₂₀heterocycyl(C═O)O— or(C₃-C₇)cyclolalkyl(C═O)O—, is independently, optionally substituted withone or more oxo, halogen, hydroxy, NH₂, CN, N₃, N(R^(a))₂, NHR^(a), SH,SR^(a), S(O)_(p)R^(a), OR^(a), (C₁-C₅)alkyl, (C₁-C₈)haloalkyl,—C(O)R^(a), —C(O)H, —C(═O)OR^(a), —C(═O)OH, —C(═O)N(R^(a))₂,—C(═O)NHR^(a), —C(═O)NH₂, NHS(O)_(p)R^(a), NR^(a)S(O)_(p)R^(a),NHC(O)R^(a), NR^(a)C(O)R^(a), NHC(O)OR^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NHR^(a), NR^(a)C(O)N(R^(a))₂, NR^(a)C(O)NH₂, NHC(O)NHR^(a),NHC(O)N(R^(a))₂, NHC(O)NH₂, ═NH, ═NOH, ═NOR^(a), NR^(a)S(O)_(p)NHR^(a),NR^(a)S(O)_(p)N(R^(a))₂, NR^(a)S(O)_(p)NH₂, NHS(O)_(p)NHR^(a),NHS(O)_(p)N(R^(a))₂, NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a);and

each R^(a) is independentl (C₁-C₈)alkyl(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl, wherein an(C₁-C₈)alkyl(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl of R^(a)is optionally substituted with one or more OH, NH₂, CO₂H, C₂-C₂₀heterocyclyl, and wherein any aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀heterocyclyl, (C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl ofR^(a) is optionally substituted with one or more OH, NH₂, CO₂H, C₂-C₂₀heterocyclyl or (C₁-C₈)alkyl.

It is to be understood that the point of connection of the esters(R^(a)O)₂P(═O)O—, (HO)₂P(═O)O—(C₁-C₈)alkyl(C═O)O—, C₆-C₂₀aryl(C═O)O—.C₂-C₂₀heterocycyl(C═O)O— and (C₃-C₇)cyclolalkyl(C═O)O— to the compoundof the invention is through the oxygen of the ester.

Preparation of Compounds of the Invention

The compounds of formula I and compounds 1-103 were be prepared by theprocedures described in examples 1-237 presented herein below. It is tobe understood that related compounds to those described can be preparedby varying these procedures or using other synthetic procedures and suchsynthetic variations are well within the grasp of the practitioner.General schemes 1-9 are provided as additional embodiments of theinvention and describe methods that can be used to prepare compounds ofthe invention.

General Scheme 1 describes the methods under which the compounds of theinvention A7 can be prepared. The starting material is a protected (PG)cycloaminoalkyl ring that can be 6-, 7- or larger size ring and alsooptionally contain substituents around the ring. This cycloaminoalkylring is substituted at the carbon atom adjacent to the nitrogen groupwith a methyl ester group. In one embodiment the stereochemistry at thisposition is the (S) stereochemistry. Protecting groups on thecycloaminoalkyl nitrogen can be removed during the synthesis usingmethods described in Green and Wutts, Protecting Groups in OrganicSynthesis 3rd Edition. In the forward scheme, the carboxylic acid methylester group on N-protected cycloaminoalkyl A1 is first converted to theenol ether utilizing a solution of Tebbe Reagent to yield A2. Typicallythe ester is reacted with the Tebbe reagent at low temperature (−78° C.)and in a suitable solvent (e.g., dry THF). The product A2 is thentransformed into alpha-bromo ketone A3 via bromination of enol ether.This transformation is carried out using bromination reagents such asNBS in a mixed solvent (e.g. THF and water). Formation ofimidazopyridine A5 is then achieved via condensation of A3 with a2-aminopyridine e.g. A4 in the presence of a base e.g. sodiumbicarbonate under elevated temperatures. Removal of the protecting groupon the cycloalkylamine e.g. BOC or CBZ is done using proceduresdescribed in Green and Wutts, Protecting Groups in Organic Synthesis 3rdEdition to provide A6. For example BOC groups are removed using TFA inan organic solvent (e.g. dichloromethane), or treatment with phosphoricacid. The unprotected NH in the cycloaminoalkyl ring on A6 is acylatedto provide compounds of structure A7 using standard acylationprocedures. For example an acid chloride, generated from thecorresponding acid using thionyl chloride or oxalyl chloride, is reactedwith A6 in the presence of an organic base, e.g. triethylamine, in anorganic solvent e.g. dichloromethane. Alternatively, a peptide couplingof A6 with an acid can be performed using a variety of standard couplingagents. For example, A6 is acylated by first, combining HATU and theacid together in an organic solvent e.g. DMF, and then after a shortperiod of time e.g. 30 min adding the amine A6 and an organic base e.g.triethylamine to generate A7

General Scheme 2 describes the methods under which the compounds of theinvention B6 can be prepared. The starting material A3 (generalscheme 1) is a protected (PG) cycloaminoalkyl ring that can be 6-, 7- orlarger size ring and also optionally contain substituents around thering. This cycloaminoalkyl ring is substituted at the carbon atomadjacent to the nitrogen group with a halo ketone. In one embodiment thestereochemistry at this position is the (S) stereochemistry. Protectinggroups on the cycloaminoalkyl nitrogen can be removed during thesynthesis using methods described in Green and Wutts, Protecting Groupsin Organic Synthesis 3rd Edition. Condensation of A3 with substituted6-chloropyridazin-3-amines B1 at elevated temperatures in an organicsolvent e.g. ethanol, leads to imidazopyridazine scaffold B2. Removal ofthe protecting group on the cycloalkylamine e.g. BOC or CBZ is doneusing procedures described in Green and Wutts, Protecting Groups inOrganic Synthesis 3rd Edition to provide B3. For example BOC groups areremoved using TFA in an organic solvent (e.g. dichloromethane) ortreatment with phosphoric acid. The unprotected NH in thecycloaminoalkyl ring on B3 is acylated to provide compounds of structureB4 using standard acylation procedures. For example an acid chloride,generated from the corresponding acid using thionyl chloride or oxalylchloride, is reacted with B3 in the presence of an organic base, e.g.triethylamine, in an organic solvent e.g. dichloromethane.Alternatively, a peptide coupling of B3 with an acid can be performedusing a variety of standard coupling agents. For example B3 is acylatedby first, combining HATU and the acid together in an organic solvente.g. DMF, and then after a short period of time e.g. 30 min adding theamine B3 and an organic base e.g. triethylamine to generate B4.

Displacement of the chloride in B4 with nucleophilic amines is thenperformed to form B5. Typically treatment of B4 in the presence of abase e.g. triethylamine and the appropriate amine at elevatedtemperatures above 50° C. forms B5. If necessary, any protecting groupsremaining on compounds B5 are then removed using conditions as describedin Green and Wutts, Protecting Groups in Organic Synthesis 3rd Editionto yield compounds of type B6.

An alternative sequence of steps can also be utilized to convert B3 toB5. Imidazo-chloropyridazine B3 is reacted with an amine in the presenceof a base e.g. triethylamine at elevated temperatures above 50 C todisplace the chloride and form B7. The unprotected NH in thecycloaminoalkyl ring on B7 is then acylated as described above toprovide compounds of structure B5.

General scheme 3 describes the methods under which the compounds of theinvention C5 can be prepared. The starting material is a protected (PG)cycloaminoalkyl ring A1 that can be 6-, 7- or larger size ring and alsooptionally contain substituents around the ring. This cycloaminoalkylring is substituted at the carbon atom adjacent to the nitrogen groupwith an ester group. In one embodiment the stereochemistry at thisposition is the (S) stereochemistry. Protecting groups on thecycloaminoalkyl nitrogen can be removed during the synthesis usingmethods described in Green and Wutts, Protecting Groups in OrganicSynthesis 3rd Edition. The N-protected cyclic aminoheterocycle A1 isfirst reacted with the anion of the alpha-methyl substituted pyridine toform C1. For example, the anion is generated first by treatment of thepyridine reagent in an organic solvent such as THF with base, preferred(but not limited to) are bases such as BuLi, NaHMDS, LDA or KOi-Bu andthen adding A1. The intermediate C1 is then converted to C2 by treatmentwith hydroxylamine. A typical produce includes treatment of the ketonein ethanolic solution with hydroxylamine in the presence of sodiumacetate to provide C2. In the next step, the pyridine nitrogen in C2 isaminated by using a variety of reagents described in the literature forthis transformation, such as hydroxylamine-o-sulphonic acid,O-(diphenyl-phosphinyl)hydroxylamine/hydrogen iodide,O-(2,4-dinitrophenyl)hydroxylamine and the like. Typically C2 isdissolved in a suitable organic solvent (e.g. acetonitrile) and treatedwith the amination reagent in the presence of base, e.g. cesiumcarbonate. The corresponding aminated pyridine, can often be reacted insitu to form the desired cyclised product C3, or alternatively additionof acid or base can facilitate this transformation to C3. The product C3is then converted to C4 and then C5 as described in Scheme 1 forconversion of A5 to A7 via A6.

General scheme 4 describes the methods under which the compounds of theinvention D6 can be prepared. The starting material is a protected (PG)cycloaminoalkyl ring that can be 6-, 7- or larger size ring and alsooptionally contain substituents around the ring. This cycloaminoalkylring is substituted at the carbon atom adjacent to the nitrogen groupwith a methyl ester group. In one embodiment the stereochemistry at thisposition is the (S) stereochemistry. Protecting groups on thecycloaminoalkyl nitrogen can be removed during the synthesis usingmethods described in Green and Wutts, Protecting Groups in OrganicSynthesis 3rd Edition. The ester group on the N-protected cyclicaminoheterocycle A1 is first converted to an alkyne D2 via one of themany methods known in the literature, typically via the correspondingaldehyde analog of A1. The aldehyde for example, is formed throughreduction of the ester group, using DIBAL in a suitable organic solvent(e.g. dichloromethane, THF, and the like). Conversion of the aldehyde tothe alkyne can be achieved by several efficient methods documented inthe literature, Corey-Fuchs, Ohira Bestmann reagent and the like. Forexample, coupling of the aldehyde with triphenylphosphine and carbontetrabromide in an organic solvent (e.g. dichloromethane) forms theintermediate dibromoalkene, which is then treated with strong base e.g.nBuLi, in THF at −78 C to generate the alkyne. Alternatively,base-promoted reactions of dialkyl (diazomethyl) phosphonates (OhiraBestmann) or (diazomethyl)-trimethylsilane with aldehydes and arylketones lead directly to the corresponding homologous alkynes. Forexample, treatment of the aldehyde with the Ohira-Bestmann phosphonatereagent in the presence of potassium carbonate in an alcoholic solventgenerates the alkyne. The alkyne is then reacted with a bromopyridineunder typically, but not limited to, Sonogashira-type conditions andtheir many variations. For example, treatment of the alkyne D2 with thehalogenated pyridine in triethylamine in the presence of CuI and apalladium (II) catalyst e.g. PdCl₂(PPh₃)₂ provides D3. The resultingpyridyl alkyne often cyclizes under the reaction conditions to theproduct D4 or alternatively can be reacted with a fluoride base e.g.TBAF or catalytic amounts of a transition metal to undergo thecyclisation. The product D4 is then converted to D5 and then D6 asdescribed in Scheme 1 for conversion of A5 to A7 via A6.

General scheme 5 describes the methods under which the compounds of theinvention E9 can be prepared. The starting material is a protected (PG)cycloaminoalkyl ring that can be 6-, 7- or larger size ring and alsooptionally contain substituents around the ring. This cycloaminoalkylring is substituted at the carbon atom adjacent to the nitrogen groupwith an acid group. In one embodiment the stereochemistry at thisposition is the (S) stereochemistry. Protecting groups on thecycloaminoalkyl nitrogen can be removed during the synthesis usingmethods described in Green and Wutts, Protecting Groups in OrganicSynthesis 3rd Edition. The carboxylic acid E1 is first activated with asuitable leaving group, for example imidazole. The imidazole product E2is typically generated by treatment of the carboxylic acid withcarbonyldiimidazole in an inert organic solvent. Once the acid isactivated as the acylimidazole E2, the addition to nitromethane anion isperformed. The anion is generated from nitromethane and a strong base(e.g. potassium tert-butoxide), in a solvent such as DMSO, to which E2is then added to form E3. Reduction of the nitro ketone is thenperformed to provide E4 using one of a variety of methods described inthe literature for reduction of nitro groups. For example, a solution ofthe nitro compound in ethanol and acetic acid, is reduced with hydrogengas in the presence of palladium on carbon to generate the amino ketoneintermediate E4. Reaction of the amino ketone with1H-pyrazole-1-carboximidamide then generates the amino imidazoleintermediate E5. This conversion is carried out in the presence of basee.g. sodium carbonate in organic solvent such as ethanol/acetic acid.Intermediate E5 is used to form bicyclic heterocycle E6 throughcondensation reactions with unsubstituted and substituted malonates inthe presence of a base. For example, dimethyl malonate is added to theintermediate E5 in ethanol and treated with sodium ethoxide, followed byheating to provide E6 where Rx is H. Treatment of E6 with neat POCl₃under elevated temperature then affords the dichloride E7. Under the POC13 conditions acidic labile protecting groups e.g. BOC are typicallyremoved, but if this is partial, further treatment with acid e.g. 4N HClin dioxane can be used to remove remaining BOC protected material. Ifother protecting groups are utilized then procedures described in Greenand Wutts, Protecting groups in Organic Synthesis 3rd Edition can beused to remove the protecting group. Displacement of the aromaticchlorides is then effected with a variety of nucleophiles. A typicalnucleophile would be an amine for example that can be reacted in theabsence or presence of a base such as triethylamine to form E5. Theunprotected NH in the cycloaminoalkyl ring is then acylated to E9 asdescribed in general Scheme 1 for formation of A7 from A6. If E9requires subsequent removal of a protecting group, this is achievedusing conditions as described in Green and Wutts, Protecting groups inOrganic Synthesis 3rd Edition.

Scheme 1 describes the methods under which the compounds of theinvention F5 can be prepared. The starting material is aldehyde F1described above. The aldehyde F1 is first condensed with ahydrazinecarboximidamide and after auto-oxidation generates the aminotriazole F2. In one embodiment the stereochemistry of the carbon bearingthe aldehyde for F1 is the (S) stereochemistry. Typically this isperformed in an organic solvent e.g. DMF. This key intermediate F2 isthen used to form the bicyclic heterocycle F3 with different side chainsthrough different condensation reactions. For example, condensation witha 1,3-dicarbonyl compound to form the heterocycle F3 where R¹, R⁸=Me andR⁷═H. Typically, the amino triazole F2 is heated with acetyl acetone inan organic solvent e.g. DMF in the presence of a base e.g. cesiumcarbonate. The product F3 is then converted to F4 and then F5 asdescribed in Scheme 1 for conversion of A5 to A7 via A6.

General scheme 7 describes the methods under which the compounds of theinvention G7 can be prepared. The starting material is aldehyde F1described above and is treated with aminopyridinium intermediates andthen cyclised to form the target heterocycles. For example, ethylO-mesityl sulfonyl acetohydroxanate is treated with 70% HClO₄ in dioxaneto form the sulfonic acid ammonium salt G2, which is then reacted withan aminopyridine G3 to form the aminopyridinium salt G4. Typically G3 istreated with the reagent G2 in an organic solvent such asdichloromethane to form G4. Condensation of G4 with aldehyde F1 affordstriazolopyridine G5. In this step a typical procedure is to heat themixture in an organic solvent e.g. DMF in the presence of base e.g.triethylamine. The product G5 is then converted to G6 and then G7 asdescribed in Scheme 1 for conversion of A5 to A7 via A6.

General scheme 8 describes the methods under which the compounds of theinvention H4 can be prepared. The starting material is bromo ketone A3described above. Compound A3 is reacted with a pyridazine H2. Typically,treatment of the bromo ketone A3 in organic solvent e.g. acetonitrile atelevated temperature effects the initial condensation, and then additionof DBU followed by further heating effects the cyclization to afford H1.The product H1 is then converted to H3 and then H4 as described inScheme 1 for conversion of A5 to A7 via A6.

General scheme 9 describes the methods under which the compounds of theinvention 15 can be prepared. The starting material is acid E1 describedabove. Acid E1 is first coupled to a diaminopyridine 12 in the presenceof an amide coupling reagent followed by subsequent cyclization in thepresence of acid to form heterocycle 13. Typically, compound E1 isreacted with diamino pyridine 12 in an organic solvent e.g. DMF, and inthe presence of a coupling reagent, e.g. HATU and base, e.g.triethylamine. The mixture is then treated with acid e.g. HOAc andheated at elevated temperature 170° C. to form 13. The product 13 isthen converted to 14 and then 15 as described in Scheme 1 for conversionof A5 to A7 via A6.

Pharmaceutical Formulations

The compounds disclosed herein are formulated with conventional carriersand excipients, which will be selected in accord with ordinary practice.Tablets will contain excipients, glidants, fillers, binders and thelike. Aqueous formulations are prepared in sterile form, and whenintended for delivery by other than oral administration generally willbe isotonic. All formulations will optionally contain excipients such asthose set forth in the “Handbook of Pharmaceutical Excipients” (1986).Excipients include ascorbic acid and other antioxidants, chelatingagents such as EDTA, carbohydrates such as dextran,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers and optionally other therapeuticingredients, particularly those additional therapeutic ingredients asdiscussed herein. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation andphysiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For infections of the eye or other external tissues e.g. mouth and skin,the formulations are preferably applied as a topical ointment or creamcontaining the active ingredient(s) in an amount of, for example, 0.075to 20% w/w (including active ingredient(s) in a range between 0.1% and20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention comprisea combination according to the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally-occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally-occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to10%, and particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns, such as0.5, 1, 30, 35 etc., which is administered by rapid inhalation throughthe nasal passage or by inhalation through the mouth so as to reach thealveolar sacs. Suitable formulations include aqueous or oily solutionsof the active ingredient. Formulations suitable for aerosol or drypowder administration may be prepared according to conventional methodsand may be delivered with other therapeutic agents such as compoundsheretofore used in the treatment or prophylaxis of Pneumovirinaeinfections as described below.

In another aspect, the invention is a novel, efficacious, safe,nonirritating and physiologically compatible inhalable compositioncomprising a compound disclosed herein, or a pharmaceutically acceptablesalt thereof (e.g., a compound of formula I or a pharmaceuticallyacceptable salt thereof or a compound of formulas 1-103 or apharmaceutically acceptable salt thereof), suitable for treatingPneumovirinae infections and potentially associated bronchiolitis.Preferred pharmaceutically acceptable salts are inorganic acid saltsincluding hydrochloride, hydrobromide, sulfate or phosphate salts asthey may cause less pulmonary irritation. Preferably, the inhalableformulation is delivered to the endobronchial space in an aerosolcomprising particles with a mass median aerodynamic diameter (MMAD)between about 1 and about 5 μm. Preferably, the compound disclosedherein, or a pharmaceutically acceptable salt thereof (e.g., a compoundof formula 1 or a pharmaceutically acceptable salt thereof or a compoundof formulas 1-103 or a pharmaceutically acceptable salt thereof) isformulated for aerosol delivery using a nebulizer, pressurized metereddose inhaler (pMDI), or dry powder inhaler (DPI).

Non-limiting examples of nebulizers include atomizing, jet, ultrasonic,pressurized, vibrating porous plate, or equivalent nebulizers includingthose nebulizers utilizing adaptive aerosol delivery technology (Denyer,J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S10). Ajet nebulizer utilizes air pressure to break a liquid solution intoaerosol droplets. An ultrasonic nebulizer works by a piezoelectriccrystal that shears a liquid into small aerosol droplets. A pressurizednebulization system forces solution under pressure through small poresto generate aerosol droplets. A vibrating porous plate device utilizesrapid vibration to shear a stream of liquid into appropriate dropletsizes.

In a preferred embodiment, the formulation for nebulization is deliveredto the endobronchial space in an aerosol comprising particles with aMMAD predominantly between about 1 μm and about 5 μm using a nebulizerable to aerosolize the formulation of a compound disclosed herein, or apharmaceutically acceptable salt thereof (e.g., a compound of formula Ior a pharmaceutically acceptable salt thereof or a compound of formulas1-103 or a pharmaceutically acceptable salt thereof) into particles ofthe required MMAD. To be optimally therapeutically effective and toavoid upper respiratory and systemic side effects, the majority ofaerosolized particles should not have a MMAD greater than about 5 μm. Ifan aerosol contains a large number of particles with a MMAD larger than5 μm, the particles are deposited in the upper airways decreasing theamount of drug delivered to the site of inflammation andbronchoconstriction in the lower respiratory tract. If the MMAD of theaerosol is smaller than about 1 μm, then the particles have a tendencyto remain suspended in the inhaled air and are subsequently exhaledduring expiration.

When formulated and delivered according to the method of the invention,the aerosol formulation for nebulization delivers a therapeuticallyefficacious dose of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof (e.g., a compound of formula I or apharmaceutically acceptable salt thereof or a compound of formulas 1-103or a pharmaceutically acceptable salt thereof) to the site ofPneumovirinae infection sufficient to treat the Pneumovirinae infection.The amount of drug administered must be adjusted to reflect theefficiency of the delivery of a therapeutically efficacious dose of acompound disclosed herein, or a pharmaceutically acceptable saltthereof. In a preferred embodiment, a combination of the aqueous aerosolformulation with the atomizing, jet, pressurized, vibrating porousplate, or ultrasonic nebulizer permits, depending on the nebulizer,about, at least, 20, to about 90%, typically about 70% delivery of theadministered dose of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof (e.g., a compound of formula I or apharmaceutically acceptable salt thereof or a compound of formulas 1-103or a pharmaceutically acceptable salt thereof). In a preferredembodiment, at least about 30 to about 50% of the active compound isdelivered. More preferably, about 70 to about 90% of the active compoundis delivered.

In another embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof (e.g., a compound of formula Ior a pharmaceutically acceptable salt thereof or a compound of formulas1-103 or a pharmaceutically acceptable salt thereof), is delivered as adry inhalable powder. The compounds of the invention are administeredendobronchially as a dry powder formulation to efficacious deliver fineparticles of compound into the endobronchial space using dry powder ormetered dose inhalers. For delivery by DPI, the compound disclosedherein is processed into particles with, predominantly, MMAD betweenabout 1 μm and about 5 μm by milling spray drying, critical fluidprocessing, or precipitation from solution. Media milling, jet millingand spray-drying devices and procedures capable of producing theparticle sizes with a MMAD between about 1 μm and about 5 μm are wellknown in the art. In one embodiment, excipients are added to thecompound disclosed herein, or a pharmaceutically acceptable salt thereof(e.g., a compound of formula I or a pharmaceutically acceptable saltthereof or a compound of formulas 1-103 or a pharmaceutically acceptablesalt thereof) before processing into particles of the required sizes. Inanother embodiment, excipients are blended with the particles of therequired size to aid in dispersion of the drug particles, for example byusing lactose as an excipient.

Particle size determinations are made using devices well known in theart. For example a multi-stage Anderson cascade impactor or othersuitable method such as those specifically cited within the USPharmacopoeia Chapter 601 as characterizing devices for aerosols withinmetered-dose and dry powder inhalers.

In another preferred embodiment, compound disclosed herein, or apharmaceutically acceptable salt thereof (e.g., a compound of formula Ior a pharmaceutically acceptable salt thereof or a compound of formulas1-103 or a pharmaceutically acceptable salt thereof) is delivered as adry powder using a device such as a dry powder inhaler or other drypowder dispersion devices. Non-limiting examples of dry powder inhalersand devices include those disclosed in U.S. Pat. No. 5,458,135; U.S.Pat. No. 5,740,794; U.S. Pat. No. 5,775,320; U.S. Pat. No. 5,785,049;U.S. Pat. No. 3,906,950; U.S. Pat. No. 4,013,075; U.S. Pat. No.4,069,819; U.S. Pat. No. 4,995,385; U.S. Pat. No. 5,522,385; U.S. Pat.No. 4,668,218; U.S. Pat. No. 4,667,668; U.S. Pat. No. 4,805,811 and U.S.Pat. No. 5,388,572. There are two major designs of dry powder inhalers.One design is a metering device in which a reservoir for the drug isplace within the device and the patient adds a dose of the drug into theinhalation chamber. The second design is a factory-metered device inwhich each individual dose has been manufactured in a separatecontainer. Both systems depend on the formulation of the drug into smallparticles of MMAD from 1 μm and about 5 μm, and often involveco-formulation with larger excipient particles such as, but not limitedto, lactose. Drug powder is placed in the inhalation chamber (either bydevice metering or by breakage of a factory-metered dosage) and theinspiratory flow of the patient accelerates the powder out of the deviceand into the oral cavity. Non-laminar flow characteristics of the powderpath cause the excipient-drug aggregates to decompose, and the mass ofthe large excipient particles causes their impaction at the back of thethroat, while the smaller drug particles are deposited deep in thelungs. In preferred embodiments, compound disclosed herein, or apharmaceutically acceptable salt thereof (e.g., a compound of formula Ior a pharmaceutically acceptable salt thereof or a compound of formulas1-103 or a pharmaceutically acceptable salt thereof), is delivered as adry powder using either type of dry powder inhaler as described herein,wherein the MMAD of the dry powder, exclusive of any excipients, ispredominantly in the range of 1 μm to about 5 μm.

In another preferred embodiment, compound disclosed herein, or apharmaceutically acceptable salt thereof (e.g., a compound of formula Ior a pharmaceutically acceptable salt thereof or a compound of formulas1-103 or a pharmaceutically acceptable salt thereof) is delivered as adry powder using a metered dose inhaler. Non-limiting examples ofmetered dose inhalers and devices include those disclosed in U.S. Pat.No. 5,261,538; U.S. Pat. No. 5,544,647; U.S. Pat. No. 5,622,163; U.S.Pat. No. 4,955,371; U.S. Pat. No. 3,565,070; U.S. Pat. No. 3,361,306 andU.S. Pat. No. 6,116,234. In preferred embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof (e.g., a compoundof formula I or a pharmaceutically acceptable salt thereof or a compoundof formulas 1-103 or a pharmaceutically acceptable salt thereof), isdelivered as a dry powder using a metered dose inhaler wherein the MMADof the dry powder, exclusive of any excipients, is predominantly in therange of about 1-5 μm.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention are used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention (“controlled release formulations”) in whichthe release of the active ingredient are controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given active ingredient.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses) or against an active viralinfection, the method of delivery, and the pharmaceutical formulation,and will be determined by the clinician using conventional doseescalation studies. It can be expected to be from about 0.0001 to about100 mg/kg body weight per day; typically, from about 0.01 to about 10mg/kg body weight per day; more typically, from about 0.01 to about 5mg/kg body weight per day; most typically, from about 0.05 to about 0.5mg/kg body weight per day. For example, the daily candidate dose for anadult human of approximately 70 kg body weight will range from 1 mg to1000 mg, preferably between 5 mg and 500 mg, and may take the form ofsingle or multiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, pulmonary,topical (including buccal and sublingual), vaginal and parenteral(including subcutaneous, intramuscular, intravenous, intradermal,intrathecal and epidural), and the like. It will be appreciated that thepreferred route may vary with for example the condition of therecipient. An advantage of the compounds of this invention is that theyare orally bioavailable and can be dosed orally.

Combination Therapy

Compositions of the invention are also used in combination with otheractive ingredients. For the treatment of Pneumovirinae virus infections,preferably, the other active therapeutic agent is active againstPneumovirinae virus infections, particularly respiratory syncytial virusinfections. Non-limiting examples of these other active therapeuticagents are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®),MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771,ALN-RSV01, ALX-0171 and mixtures thereof.

Many of the infections of the Pneumovirinae viruses are respiratoryinfections. Therefore, additional active therapeutics used to treatrespiratory symptoms and sequelae of infection may be used incombination with the compounds disclosed herein, or a pharmaceuticallyacceptable salt thereof (e.g., a compound of formula I or apharmaceutically acceptable salt thereof or a compound of formulas 1-103or a pharmaceutically acceptable salt thereof). The additional agentsare preferably administered orally or by direct inhalation. For example,other preferred additional therapeutic agents in combination with thecompounds disclosed herein for the treatment of viral respiratoryinfections include, but are not limited to, bronchodilators andcorticosteroids.

Glucocorticoids, which were first introduced as an asthma therapy in1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the mostpotent and consistently effective therapy for this disease, althoughtheir mechanism of action is not yet fully understood (Morris, J.Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oralglucocorticoid therapies are associated with profound undesirable sideeffects such as truncal obesity, hypertension, glaucoma, glucoseintolerance, acceleration of cataract formation, bone mineral loss, andpsychological effects, all of which limit their use as long-termtherapeutic agents (Goodman and Gilman, 10th edition, 2001). A solutionto systemic side effects is to deliver steroid drugs directly to thesite of inflammation. Inhaled corticosteroids (ICS) have been developedto mitigate the severe adverse effects of oral steroids. Non-limitingexamples of corticosteroids that may be used in combinations with thecompound disclosed herein, or a pharmaceutically acceptable salt thereof(e.g., a compound of formula I or a pharmaceutically acceptable saltthereof or a compound of formulas 1-103 or a pharmaceutically acceptablesalt thereof) are dexamethasone, dexamethasone sodium phosphate,fluorometholone, fluorometholone acetate, loteprednol, loteprednoletabonate, hydrocortisone, prednisolone, fludrocortisones,triamcinolone, triamcinolone acetonide, betamethasone, beclomethasonediproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide,flunisolide, fluocortin-21-butylate, flumethasone, flumetasonc pivalate,budesonide, halobetasol propionate, mometasone furoate, fluticasonepropionate, ciclesonide; or a pharmaceutically acceptable salts thereof.

Other anti-inflamatory agents working through anti-inflamatory cascademechanisms are also useful as additional therapeutic agents incombination with the compounds disclosed herein, or a pharmaceuticallyacceptable salt thereof (e.g., compounds of formula I or apharmaceutically acceptable salt thereof or compound of formulas 1-103or a pharmaceutically acceptable salt thereof) for the treatment ofviral respiratory infections. Applying “anti-inflammatory signaltransduction modulators” (referred to in this text as AISTM), likephosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific),transcription factor inhibitors (e.g., blocking NFκB through IKKinhibition), or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K,EGFR or Syk) is a logical approach to switching off inflammation asthese small molecules target a limited number of common intracellularpathways—those signal transduction pathways that are critical points forthe anti-inflammatory therapeutic intervention (see review by P. J.Barnes, 2006). These non-limiting additional therapeutic agents include:5-(2,4-Difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid(2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797);3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluorormethoxy-benzamide(PDE-4 inhibitor Roflumilast);4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4inhibitor CDP-840);N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide(PDE-4 inhibitor Oglemilast);N-(3,5-Dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide(PDE-4 inhibitor AWD 12-281);8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid(3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591);4-[5-(4-Fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine(P38 inhibitor SB-203850);4-[4-(4-Fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol(P38 inhibitor RWJ-67657);4-Cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast,PDE-4 inhibitor);(3-Chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine(Gefitinib, EGFR inhibitor); and4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide(Imatinib, EGFR inhibitor).

Combinations comprising inhaled β2-adrenoreceptor agonistbronchodilators such as formoterol, albuterol or salmeterol with acompound disclosed herein, or a pharmaceutically acceptable salt thereof(e.g., a compound of formula I or a pharmaceutically acceptable saltthereof or a compound of formulas 1-103 or a pharmaceutically acceptablesalt thereof) are also suitable, but non-limiting, combinations usefulfor the treatment of respiratory viral infections.

Combinations of inhaled β2-adrenoreceptor agonist bronchodilators suchas formoterol or salmeterol with ICS's are also used to treat both thebronchoconstriction and the inflammation (Symbicort® and Advair®,respectively). The combinations comprising these ICS andβ2-adrenoreceptor agonist combinations along with the compoundsdisclosed herein are also suitable, but non-limiting, combinationsuseful for the treatment of respiratory viral infections.

For the treatment or prophylaxis of pulmonary broncho-constriction,anticholinergics are of potential use and, therefore, useful as anadditional therapeutic agents in combination with a compound disclosedherein, or a pharmaceutically acceptable salt thereof (e.g., a compoundof formula I or a pharmaceutically acceptable salt thereof or a compoundof formulas 1-103 or a pharmaceutically acceptable salt thereof) for thetreatment of viral respiratory infections. These anticholinergicsinclude, but are not limited to, antagonists of the muscarinic receptor(particularly of the M3 subtype) which have shown therapeutic efficacyin man for the control of cholinergic tone in COPD (Witek, 1999);1-{4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylicacid (1-methyl-piperidin-4-ylmethyl)-amide;3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane(Ipratropium-N,N-diethylglycinate);1-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid1-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin);2-Hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid1-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate);2-{1-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide(Darifenacin); 4-Azepan-1-yl-2,2-diphenyl-butyramide (Buzepide);7-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(Oxitropium-N,N-diethylglycinate);7-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(Tiotropium-N,N-diethylglycinate); Dimethylamino-acetic acid2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester(Tolterodine-N,N-dimethylglycinate);3-[4,4-Bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium;1-[1-(3-Fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one;1-Cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol;3-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1azonia-bicyclo[2.2.2]octane(Aclidinium-N,N-diethylglycinate); or(2-Diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester.

The compounds of formula I or a compound of formulas 1-103 may also becombined with mucolytic agents to treat both the infection and symptomsof respiratory infections. A non-limiting example of a mucolytic agentis ambroxol. Similarly, the compounds of formula I or the compounds offormulas 1-103 may be combined with expectorants to treat both theinfection and symptoms of respiratory infections. A non-limiting exampleof an expectorant is guaifenesin.

Nebulized hypertonic saline is used to improve immediate and long-termclearance of small airways in patients with lung diseases (Kuzik, J.Pediatrics 2007, 266). The compounds of formula I or the compounds offormulas 1-103 may also be combined with nebulized hypertonic salineparticularly when the Pneumovirinae virus infection is complicated withbronchiolitis. The combination of the compounds of formula I or thecompounds of formulas 1-103 with hypertonic saline may also comprise anyof the additional agents discussed above. In a preferred aspect,nebulized about 3% hypertonic saline is used.

It is also possible to combine any compound of the invention with one ormore additional active therapeutic agents in a unitary dosage form forsimultaneous or sequential administration to a patient. The combinationtherapy may be administered as a simultaneous or sequential regimen.When administered sequentially, the combination may be administered intwo or more administrations.

Co-administration of a compound of the invention with one or more otheractive therapeutic agents generally refers to simultaneous or sequentialadministration of a compound of the invention and one or more otheractive therapeutic agents, such that therapeutically effective amountsof the compound of the invention and one or more other activetherapeutic agents are both present in the body of the patient.

Co-administration includes administration of unit dosages of thecompounds of the invention before or after administration of unitdosages of one or more other active therapeutic agents, for example,administration of the compounds of the invention within seconds,minutes, or hours of the administration of one or more other activetherapeutic agents. For example, a unit dose of a compound of theinvention can be administered first, followed within seconds or minutesby administration of a unit dose of one or more other active therapeuticagents. Alternatively, a unit dose of one or more other therapeuticagents can be administered first, followed by administration of a unitdose of a compound of the invention within seconds or minutes. In somecases, it may be desirable to administer a unit dose of a compound ofthe invention first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of one or more other activetherapeutic agents. In other cases, it may be desirable to administer aunit dose of one or more other active therapeutic agents first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound of the invention.

The combination therapy may provide “synergy” and “synergistic”, i.e.the effect achieved when the active ingredients used together is greaterthan the sum of the effects that results from using the compoundsseparately. A synergistic effect may be attained when the activeingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g. in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together. A synergisticanti-viral effect denotes an antiviral effect which is greater than thepredicted purely additive effects of the individual compounds of thecombination.

One embodiment provides for methods of treating a Pneumovirinae virusinfection (e.g., a Human respiratory syncytial virus infection) in apatient (e.g., a human), comprising administering to the patient atherapeutically effective amount of a compound of formula I or acompound of formulas 1-103, or a pharmaceutically acceptable salt,solvate, and/or ester thereof.

One embodiment provides for methods of treating a Pneumovirinae virusinfection in a patient (e.g., a human), comprising administering to thepatient a therapeutically effective amount of a compound of formula I ora compound of formulas 1-103, or a pharmaceutically acceptable salt,solvate, and/or ester thereof, and at least one additional activetherapeutic agent.

One embodiment provides for methods of treating Human respiratorysyncytial virus infection in a patient (e.g., a human), comprising:administering to the patient a therapeutically effective amount of acompound of formula I or a compound of formulas 1-103, or apharmaceutically acceptable salt, solvate, and/or ester thereof, and atleast one additional active therapeutic agent.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein, to the extent suchproducts are novel and unobvious over the prior art. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes novel andunobvious compounds produced by a process comprising contacting acompound of this invention with a mammal for a period of time sufficientto yield a metabolic product thereof. Such products typically areidentified by preparing a radiolabelled (e.g. ¹⁴C or ³H) compound of theinvention, administering it parenterally in a detectable dose (e.g.greater than about 0.5 mg/kg) to an animal such as rat, mouse, guineapig, monkey, or to man, allowing sufficient time for metabolism to occur(typically about 30 seconds to 30 hours) and isolating its conversionproducts from the urine, blood or other biological samples. Theseproducts are easily isolated since they are labeled (others are isolatedby the use of antibodies capable of binding epitopes surviving in themetabolite). The metabolite structures are determined in conventionalfashion, e.g. by MS or NMR analysis. In general, analysis of metabolitesis done in the same way as conventional drug metabolism studieswell-known to those skilled in the art. The conversion products, so longas they are not otherwise found in vivo, are useful in diagnostic assaysfor therapeutic dosing of the compounds of the invention even if theypossess no HSV antiviral activity of their own.

Recipes and methods for determining stability of compounds in surrogategastrointestinal secretions are known. Compounds are defined herein asstable in the gastrointestinal tract where less than about 50 molepercent of the protected groups are deprotected in surrogate intestinalor gastric juice upon incubation for 1 hour at 37° C. Simply because thecompounds are stable to the gastrointestinal tract does not mean thatthey cannot be hydrolyzed in vivo. The prodrugs of the inventiontypically will be stable in the digestive system but may besubstantially hydrolyzed to the parental drug in the digestive lumen,liver, lung or other metabolic organ, or within cells in general.

Tissue Distribution

It has also been discovered that certain compounds disclosed herein ofthe invention show high lung to plasma ratios which may be beneficialfor therapy. One particular group of compounds of the invention thatdemonstrate this property are compounds that include an amine functionalgroup.

Examples

Certain abbreviations and acronyms are used in describing theexperimental details. Although most of these would be understood by oneskilled in the art, Table I contains a list of many of theseabbreviations and acronyms.

TABLE 1 List of abbreviations and acronyms. Abbreviation Meaning Ac₂Oacetic anhydride AIBN 2,2′-azobis(2-methylpropionitrile) Bn benzyl BnBrbenzylbromide BSA bis(trimethylsilyl)acetamide BzCl benzoyl chloride CDIcarbonyl diimidazole DABCO 1,4-diazabicyclo[2.2.2]octane DBN1,5-diazabicyclo[4.3.0]non-5-ene DDQ2,3-dichloro-5,6-dicyano-1,4-benzoquinone DBU 1,5-diazabicyclo[5.4.0]undec-5-ene DCA dichloroacetamide DCCdicyclohexylcarbodiimide DCM dichloromethane DMAP4-dimethylaminopyridine DME 1,2-dimethoxyethane DMTCl dimethoxytritylchloride DMSO dimethylsulfoxide DMTr 4, 4′-dimethoxytrityl DMFdimethylformamide EtOAc ethyl acetate ESI electrospray ionization HMDShexamethyldisilazane HPLC High pressure liquid chromatography LDAlithium diisopropylamide LRMS low resolution mass spectrum MCPBAmeta-chloroperbenzoic acid MeCN acetonitrile MeOH methanol MMTC monomethoxytrityl chloride m/z or mfe mass to charge ratio MH⁺ mass plus 1MH⁻ mass minus 1 MsOH methanesulfonic acid MS or ms mass spectrum NBSN-bromosuccinimide Ph phenyl rt or r.t. room temperature TBAFtetrabutylammonium fluoride TMSCl chlorotrimethylsilane TMSBrbromotrimethylsilane TMSI iodotrimethylsilane TMSOTf(trimethylsilyl)trifluoromethylsulfonate TEA triethylamine TBAtributylamine TBAP tributylammonium pyrophosphate TBSClt-butyldimethylsilyl chloride TEAB triethylammonium bicarbonate TFAtrifluoroacetic acid TLC or tic thin layer chromatography Trtriphenylmethyl Tol 4-methylbenzoyl Turbo Grignard 1:1 mixture ofisopropylmagnesium chloride and lithium chloride δ parts per milliondown field from tetramethylsilane

The invention will now be illustrated by the preparation of thefollowing non-limiting compounds of the invention. It is to beunderstood that certain intermediates described herein may also becompounds of the invention.

Example 1a Preparation of Intermediate 1

A solution of 1-ethoxy-propene (5.1 mL, 46 mmol) in pyridine (3.4 mL)was added slowly via addition funnel (˜1 drop/sec) to neattrichloroacetyl chloride (4.7 mL, 42 mmol) at −10° C. under an argonatmosphere. The reaction mixture was then allowed to slowly warm to 23°C. After 20 h, the reaction mixture was diluted with dichloromethane (50mL) and the resulting mixture was washed with 0.01N HCl (3×50 mL) andbrine (50 mL), was dried over anhydrous sodium sulfate, and wasconcentrated under reduced pressure. To the crude residue was addedsodium ethoxide (21 wt % in ethanol, 7.1 g, 44 mmol) slowly via syringe.After 30 min, the reaction mixture was partitioned betweendichloromethane (500 mL) and water (500 mL). The phases were split andthe aqueous layer was extracted with dichloromethane (500 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate, andwere concentrated to afford intermediate 1 (6.8 g, 95%) as an orangeoil.

¹H-NMR (CDCl₃, 400 MHz): 7.28 (app s, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.96(q, J=7.1 Hz, 2H), 1.66 (s, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1Hz, 3H).

Example 1b Preparation of Intermediate 2

N-Boc-(S)-piperidine-2-carboxylic acid (5.0 g, 22 mmol) in DMF (100 mL)was treated with Cs₂CO₃ (3.5 g, 10.9 mmol) and MeI (1.5 mL, 24 mmol).The mixture was stirred for 4 hours and diluted with MTBE (250 mL). Themixture was washed with water (twice with 100 mL) and saturated sodiumchloride solution (100 mL). The solution was dried over anhydrous sodiumsulfate and concentrated to afford the ester intermediate 2 (5.1 gcrude, 96%) as an oil which was used without further purification

¹H NMR (CDCl₃, 300 MHz): δ 4.80 (m, 1H), 3.97 (m, 1H), 3.73 (s, 3H),2.93 (m, 1H), 2.18 (app d, J=13.2 Hz, 1H), 1.67 (m, 2H), 1.45 (br s,OH), 1.20 (app t, J=13.5 Hz, 1H). R_(f)=0.90 (30% EtOAc-hexanes);

Example 2 Preparation of Intermediate 3

(S)-1-Boc-piperidine-2-carboxylic acid (25 g, 109 mmol, Sigma-Aldrich)in DMF (500 mL) was treated sequentially with MeNHOMe.HCl (11.2 g, 115mmol), N-methylmorpholine (36 mL, 327 mmol), HOBt (16.2 g, 120 mmol),and EDCI (23 g, 120 mmol) and stirred for 18 h. The solution was dilutedwith EtOAc (1000 mL) and washed with H₂O (twice with 500 mL) andsaturated NaCl solution (500 mL). The solution was dried over MgSO₄,filtered and concentrated. The residue was subjected to a 330 g SiO₂Combiflash High Performance Gold column (0-100% EtOAc-hexanes gradient)to afford the Weinreb amide intermediate 3 (18.4 g, 61%) as a clear oil:

¹H NMR (CDCl₃, 300 MHz): δ 5.06 (br m, 1H), 3.93 (br m, 1H), 3.77 (br s,3H), 3.18 (s, 3H), 2.01 (app d, J=13.5 Hz, 1H), 1.71 (m, 4H), 1.45 (s,9H);

LCMS (ESI) m/z 273 [M+H]⁺, t_(R)=2.31 min;

HPLC (RP: 6-98% MeCN—H₂O gradient, 0.05% TFA modifier) t_(R)=4.423 min.

R_(f)=0.60 (50% EtOAc-hexanes);

Example 3 Preparation of Intermediate 4

To a solution of acetonitrile (5 ml, 93.8 mmol) in dry THF (50 ml) at−78° C. was added dropwise NaN(TMS)₂ (34 ml, 68 mmol, 2M in hexanes).The solution was warmed to −40° C. and stirred for 20 min. The solutionwas then cooled to −78° C. and a solution of the ester (Intermediate 2)(7.6 g, 31.1 mmol) in THF (20 ml) was added dropwise. The solution waswarmed up to −40° C. and stirred for 2 h. The solution was then cooledto −78° C. and a solution of acetic acid (4.8 ml, 80 mmol) in THF (20ml) was added dropwise. The solution was then warmed to room temperatureand volatiles were removed under reduced pressure at 40° C. Theresulting residue was dissolved in EtOAc (300 mL) and the organic phasewas washed 2x each with brine. Volatiles were removed under reducedpressure at 40° C.

¹H NMR (DMSO, 300 MHz): δ 4.63 (br s, 1H), 4.18-4.13 (m, 1H), 3.82-3.78(m, 1H), 3.65 (s, 2H), 2.85-2.63 (m, 1H), 1.65-1.52 (m, 9H), 1.38 (s,9H).

LCMS m/z: 153 [M-Boc group+H], t_(R)=2.50 min.

The residue was dissolved in EtOH (150 ml) and hydrazine acetate (4.5 g,47 mmol) was added. The solution was stirred for 16 h at roomtemperature. Volatiles were removed under reduced pressure at 40° C.,EtOAc added (200 ml) and the organic phase washed with aqueous diluteNaHCO₃, then H₂O followed by brine. Volatiles were removed under reducedpressure at 40° C., the resulting residue was purified by silica gelcolumn (DCM/MeOH, gradient from 0% to 20%) to afford the productintermediate 4 (7.5 g, 90%) as an oil.

LCMS m/z [M+H]⁺ C₁₃H₂₂N₄O₂ requires: 266.34. Found 266.84

HPLC (min, purity) t_(R)=2.13, 100%

¹H NMR (DMSO, 300 MHz): δ 11.20 (br s, 1H), 5.09 (m, 1H), 5.07 (s, 1H),4.67 (br s, 2H), 3.81 (app d, J=12.0 Hz, 1H), 2.72 (app br t, J=12.0 Hz,1H), 2.08 (app d, J=12.9 Hz, 1H), 1.57 (m, 4H), 1.39 (s, 9H); MS (ESI)m/z 267 [M+H]+, t_(R)=1.97 min. (3.5 min method). HPLC (Chiral:Chiralpak AD-H, isocratic n-heptane-isopropanol 70:30). t_(R)(desired)=22.42 min, t_(R) (enantiomer of desired isomer)=25.67 min; %ee=93.

Example 4 Preparation of Intermediate 4 Via Weinreb Amide

MeCN (3.20 mL, 60.7 mmol) in THF (50 mL) was cooled to −78° C. under Ar.A NaHMDS solution (1.0 M in THF, 36.8 mL, 36.8 mmol) was added dropwiseover 5 min, during which time an off-white suspension had formed. Thesuspension was warmed to −20° C. and stirred for 20 min. The suspensionwas cooled to −78° C. and transferred via cannula to the Weinreb amideintermediate 3 (5.02 g, 18.4 mmol) in THF (50 mL) at −78° C. over 5 min.The suspension is warmed to −45° C. and stirred for 3 h, during whichtime the suspension became a yellow solution. The solution was cooled to−78° C. and AcOH (4.2 mL in 10 mL THF, 73.6 mmol) was added dropwise.The solution was warmed to room temperature and diluted with EtOAc (100mL). The solution was washed with H₂O (50 mL) and saturated NaClsolution (50 mL). The solution was dried over MgSO₄ and concentrated toafford the cyano ketone as a yellow oil which was used without furtherpurification.

The crude α-cyano ketone was used in the next reaction with hydrazineacetate to synthesize desired amino pyrazole intermediate 4 as describedabove.

MS (ESI) m/z 267 [M+H]⁺, t_(R)=1.81 min.

HPLC (RP: 6-98% MeCN—H₂O gradient, 0.05% TFA modifier) t_(R)=3.212 min(>95% purity @254 nM).

HPLC (Chiral: Chiralpak AD-H 250×4.6 mm, 5 micron; isocraticn-heptane-isopropanol

70:30) t_(R) (a isomer, desired)=22.35 min, t_(R) (b isomer)=25.78 min;α=1.15; % ee=>90%.

Example 5 Preparation of Intermediate 5

Intermediate 1, (11.8 g, 67.6 mmol) and Cs₂CO₃ (22.0 g, 67.6 mmol) wereadded to a solution of intermediate 4 (12.0 g, 45.1 mmol) at roomtemperature and the reaction mixture was heated to 130° C. After 17 h,the reaction mixture was allowed to cool to room temperature and wasconcentrated under reduced pressure. The crude residue was diluted withethyl acetate (250 mL) and was filtered. The resulting filtrate wasconcentrated under reduced pressure and the residue was purified viaSiO₂ column chromatography (330 g SiO₂ Combiflash HP Gold Column, 0-100%ethyl acetate/hexanes) to afford intermediate 5 (8.58 g, 57%) as a lightyellow solid.

¹H NMR (CDCl₃, 400 MHz): δ 12.01 (br s, 1H), 7.99 (s, 1H), 5.73 (s, 1H),5.42 (br s, 1H), 4.01 (br d, J=12.2 Hz, 1H), 2.81 (br t, J=11.2 Hz, 1H),2.29 (d, J=13.5 Hz, 1H), 2.07 (d, J=1.1 Hz, 3H), 1.87-1.69 (m, 1H),1.68-1.41 (m, 4H), 1.48 (s, 9H).

¹³C NMR (CDCl₃, 100 MHz): δ 162.87, 156.34, 155.43, 140.16, 135.00,113.29, 86.50, 79.75, 28.41, 27.79, 25.27, 21.00, 19.88, 13.38.

LCMS (ESI) m/z 333.0 [M+H]⁺, t_(R)=2.24 min.

HPLC t_(R) (min), purity %: 3.969, 99%.

R_(f)=0.50 (EtOAc).

Chiral HPLC, 98% ee (Chiralpak IC 5 mM, 4.6×150 mm, 10-95% MeCN/H₂O,0.05% trifluoroacetic acid modifier) (S)-isomer t_(R)=22.234 min,(R)-isomer t_(R)=20.875 min.

Example 6 Preparation of Intermediate 6

POCl₃ (5.60 mL, 59.8 mmol) was added to intermediate 5 (993.4 mg, 2.99mmol) at room temperature and the reaction mixture was heated to 100° C.After 2 h, the reaction mixture was allowed to cool to room temperatureand was concentrated under reduced pressure to afford intermediate 6 asan orange semi-solid, which was used directly in the following step.

¹H NMR (DMSO-d₆, 400 MHz): δ 9.40 (br d, J=7.6 Hz, 1H), 9.27-9.16 (m,2H), 6.85 (s, 1H), 4.54 (t, J=112.4 Hz, 1H), 3.32 (d, J=12.8 Hz, 1H),3.08 (q, J=8.81 Hz, 1H), 2.33 (s, 3H), 2.23-2.14 (m, 1H), 1.92-1.61 (m,5H).

LCMS (ESI) m/z 251.1 [M+H]⁺, t_(R)=0.21 min.

HPLC t_(R)=2.35 min.

Example 7 Preparation of Intermediate 7

A solution of intermediate 10 (prepared from 1 g of the BOC intermediateusing formic acid as described in the synthesis of intermediate 10 ofExample 11) was dissolved in MeOH (10 ml). To the solution was addedintermediate 6 (944 mg, 3.76 mmol) and NEt₃ (2 ml). The reaction mixturewas heated at 700 overnight. The solvent was evaporated and the residuewas purified by combi-flash column chromatography (0-100% MeOH/DCM) toafford intermediate 7 (922 mg, 60%).

LCMS (m/z) 327.40[M+H]⁺

MW 326.19

Example 8 Preparation of Intermediate 8 (Cis Mixture of Isomers)

A mixture of cis/trans tert-butyl3-cyano-4-hydroxypyrrolidine-1-carboxylate was separated on a silicacolumn (200-300) eluting with EA:PE=1:10, EA:PE=1:5 to give intermediate8 (cis mixture of isomers as the earlier eluting peak, 30 g, 46%) aswhite solid. TLC (Eluent: PE:EA=1:1): Starting material cis/transmixture (R_(f)=0.4 and 0.45)

¹H NMR: (400 MHz DMSO): δ 4.60-4.48 (m, 1H), 3.8-3.65 (m, 1H), 3.51-3.63(m, 1H), 3.5-3.3 (m, 2H), 2.9-3.1 (m, 1H), 2.70 (s, 1H), 1.3-1.45 (s,9H).

Example 9 Preparation of Intermediate 9

To a mixture of intermediate 8 (10 g, 0.047 mol) and imidazole (6.4 g,0.094 mol) in DMF (100 ml) was added TBDPSCl (14.2 g, 0.05 mol) dropwiseand the mixture was stirred at room temperature overnight. Citric acid(10%) was added and extracted with EA, dried, concentrated and purifiedby silica gel column chromatography (EA:PE=1:50 to 1:25) to giveintermediate 9 as colorless oil (9 g, 60%).

TLC Information (Eluent: PE: EA=1:1), starting material R_(f)=0.40,product R_(f)=0.90

¹H NMR (400 MHz DMSO) δ 7.74-7.62 (m, 4H), 7.47-7.41 (m, 6H), 4.51 (m,1H), 3.8-3.65 (m, 1H), 3.51-3.63 (m, 1H), 3.5-3.3 (m, 2H), 2.9-3.1 (m,1H), 1.3-1.45 (s, 9H)

Example 10 Preparation of Intermediate 9a and 9b

Intermediate 9 was separated by chiral SFC (see below) to giveintermediate 9a (earlier eluting, 16.3 g, 41%) and intermediate 9b(later eluting, 16.7 g, 41%) as white solids.

Column: ChiralPak IC-H, 250×50mmI.D, mobile Phase: CO₂/iPrOH (35%isocratic), retention time (9a) 1.94 min, retention time (9b): 2.73 min.

Example 11 Preparation of Intermediate 10

To a solution of intermediate 9a (16.3 g, 0.036 mol) in CH₂Cl₂ (200 mL)at room temperature was added TBAF (8.0 g, 0.025 mol). The reactionmixture was stirred at room temperature for 30 min, then diluted withCH₂Cl₂ (500 mL) and washed with saturated aq. NH₄Cl and brine, driedover MgSO₄, filtered and concentrated. The crude product was purified bysilica gel chromatography (PE: EA=10:1 to 2:1) to afford the BOCpyrrolidine intermediate as a single cis isomer (5.9 g, yield: 76%) as awhite solid.

TLC Information (10a) (Eluent: PE:EA=1:1)

1. Starting material (R_(f)=0.90)

2. Reaction Mixture (Product: R_(f)=0.4)

¹H NMR: 400 MHz DMSO: δ 4.60-4.58 (m, 1H), 3.87-3.79 (m, 1H), 3.69-3.64(m, 1H), 3.56-3.49 (m, 2H), 2.9-3.1 (m, 1H), 1.4-1.5 (s, 9H)

The BOC pyrollidine intermediate (1 g, 4.7 mmol) was added to HCOOH (5ml) and was heated at 40° C. for 2 h. The solvent was evaporated underreduced pressure and preheated IPA (100° C.) was added to dissolve theresidue; white precipitate formed after the IPA solution cooled down.The product was filtered and washed with IPA to give intermediate 10(470 mg, 63%) that was used without further purification in subsequentreactions.

Example 12 Preparation of Intermediate 11

HATU (1.37 g, 3.59 mmol) was added to a solution of5-chloro-2-(methylsulfonamido)benzoic acid (823 mg, 3.29 mmol) in DMF(15.0 mL), and the reaction mixture was stirred at room temperature.After 1 h, a solution of crude intermediate 6 (220 mg, 2.99 mmol) in DMF(1 mL) was added followed by the addition of triethylamine (2.00 mL,14.3 mmol), and the reaction mixture was stirred at room temperature for19 h. The reaction mixture was partitioned between ethyl acetate (250mL) and saturated aqueous sodium bicarbonate solution (200 mL), and thelayers were separated. The organic layer was washed with saturatedaqueous sodium bicarbonate solution (200 mL) and saturated sodiumchloride solution (200 mL), was dried over Na₂SO₄, and was concentratedunder reduced pressure. The crude residue was purified via SiO₂ columnchromatography (12 g SiO₂ Combiflash HP Gold Column, 0-100% ethylacetate/hexanes) to afford intermediate 11 (736.2 mg, 51% (2-steps)) asa white solid.

¹H NMR (CDCl₃, 400 MHz): δ 10.05 (br s, 0.2H), 9.13 (br s, 1H), 8.95 (brs, 1H), 8.81 (br s, 0.2H), 7.70 (d, J=8.8 Hz, 1H), 7.56 (d, J 8.8 Hz,0.2H), 7.40 (dd, J=8.8, 2.4 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.31 (d,J=4.4 Hz, 0.2H), 6.45 (s, 1H), 6.40 (br s, 0.2H), 6.28 (br d, J=4.4 Hz,1H), 5.01 (br s, 0.2H), 4.54 (br d, J=14.0 Hz, 0.2H), 3.35 (br d, J=13.2Hz, 1H), 3.15-3.03 (m, 1H), 2.92 (s, 3H), 2.39 (s, 3H), 2.13-1.98 (m,1H), 1.90-1.59 (m, 2H), 1.59-1.31 (m, 3H).

¹³C NMR (CDCl₃, 100 MHz): δ 167.09, 156.12, 153.13, 147.86, 135.68,131.79, 131.66, 131.38, 130.12, 125.91, 125.44, 117.08, 93.74, 47.65,44.07, 39.81, 27.83, 25.47, 19.78, 16.90.

LCMS (ESI) m/z 482.1 [M+H]⁺, I_(R)=2.79 min.

HPLC t_(R) (min), purity %: 5.438, 99%

R_(f)=0.47 (50% EtOAc/hexanes).

Chiral HPLC, 99% ee (Chiralpak IC 5 mM, 4.6×150 mm, 10-95% MeCN/H₂O,0.05% trifluoroacetic acid modifier) (S)-isomer t_(R)=29.739 min,(R)-isomer t_(R)=29.495 min.

Example 13 Preparation of Intermediate 12

To a solution of intermediate 6 (100.0 mg, 0.35 mmol) in MeOH (1.74 mL)was added (S)-tert-butyl pyrrolidin-3-ylcarbamate (648 mg, 3.48 mmol)and triethylamine (970 μL, 6.96 mmol) at room temperature, and thereaction mixture was heated to 70° C. After 4 h, the reaction mixturewas allowed to cool to room temperature and was concentrated underreduced pressure. The crude residue was purified by preparatory HPLC(5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) to affordintermediate 12 (169 mg, 95%) as an orange solid.

LCMS (ESI) m/z 401.23 [M+H]⁺, t_(R)=1.86 min.

Example 14 Preparation of Intermediate 14

2-Amino-5-chlorobenzoic acid (82 mg, 0.48 mmol) and HATU (228 mg, 0.6mmol) were dissolved in anhydrous DMF (2 ml). After activation for 1hour, intermediate 12 (120 mg, 0.3 mmol) and triethylamine (0.17 ml)were added to the above solution. The reaction was stirred undernitrogen for 2 hours. The solvents were removed by rotary evaporation.The residue was purified with silica gel column chromatography toprovide intermediate 14. (Yield 134 mg, 81%).

LCMS m/z [M+H]⁺ C₂₈H₃₆ClN₇O₃ requires: 554.26. Found 554.18

HPLC Tr (min), purity %: 2.00, 98%

Example 15 Preparation of Intermediate 15

2-Amino-5-methylbenzoic acid (316 mg, 2.09 mmol) and HATU (992 mg, 2.61mmol) were dissolved in anhydrous DMF (2 ml). After activation for 1hour, intermediate 6 (500 mg, 1.74 mmol) and triethylamine (0.7 ml) wereadded to the above solution. The reaction was stirred under nitrogen for2 hours. The solvents were removed by rotary evaporation. The residuewas purified with silica gel column chromatography to provideintermediate 15. (Yield 320 mg, 42%).

LCMS m/z [M+H]⁺ C₂₀H₂₂ClN₅O requires: 384.15. Found 383.99

HPLC Tr (min), purity %: 2.00, 98%

Example 16 Preparation of Intermediate 16

Intermediate 15 (320 mg, 0.84 mmol) was dissolved in pyridine (2 ml).Then acetyl chloride (78 mg, 1.0 mmol) was added to the above solution.The reaction was stirred under nitrogen for 30 min. The solvents wereremoved by rotary evaporation. The residue was purified with silica gelcolumn chromatography to provide intermediate 16. (Yield 305 mg, 86%).

LCMS m/z [M+H]⁺ C₂₂H₂₄ClN₅O₂ requires: 426.16. Found 425.89

HPLC Tr (min), purity %: 2.40, 98%

Example 17 Preparation of Intermediate 18

To a solution of the pyrazole intermediate 4 (7.2 g, 27.1 mmol) inacetic acid (100 ml) was added 2-methyl acetoacetate (3.9 ml, 27.1 nM)and the solution stirred at 100° C. for 45 min. The volatiles wereremoved under reduced pressure at 40° C. and the resulting residue waspurified by silica gel column (DCM/MeOH, gradient from 0% to 20%) toafford intermediate 18 (7.23 g, 77%) as an oil.

¹H-NMR (DMSO, 400 MHz): δ 7.26 (s, 1H), 5.79 (s, 1H), 5.42 (s, 1H), 3.99(m, 1H), 2.81 (m, 1H), 2.56 (m, 1H), 2.36 (m, 3H), 2.08 (m, 3H), 1.76(m, 3H), 1.53-1.28 (m, 14H).

LCMS m/z [M+H]⁺ C₁₈H₂₆N₄O₃ requires: 346.42. Found 347.07

HPLC Tr (min), purity %: 1.45, 100%.

Example 18 Preparation of Intermediate 19

The intermediate 18 (0.3 g, 0.867 mmol), and DMAP (0.117 g, 0.958 mmol)were dissolved in anhydrous pyridine (15 mL) and placed under nitrogenwith stirring. POCl₃ (0.567 ml, 6.07 mmol) was added neat and thereaction was heated to 100° C. for 2 hours. The reaction was monitoredby LC/MS. When it was complete in about 2 hours the reaction was cooledto room temperature and solvents were removed by rotary evaporation. Theresidue was redissolved in 200 ml DCM and washed with 200 ml water. Theorganic layer was collected dried over MgSO₄(anhydrous), filtered andthen evaporated. The product was purified by column chromatography usingethyl acetate (25%) in hexanes to elute intermediate 19 (0.234 g, 0.643mmol, 74%)

¹H-NMR (CD₃CN, 300 MHz): δ 1.45 (m, 11H), 1.64 (m, 2H), 1.87 (m 1H),2.39 (m 4H), 2.55 (s, 3H), 2.95 (t, 1H), 4.04 (d, 1H), 5.57 (d, 1H),6.39 (s, 1H).

Example 19 Preparation of Intermediate 20

The starting intermediate 19 (0.06 g, 0.165 mmol), along with sodiumacetate (0.027 g, 0.330 mmol) were dissolved in absolute ethanol (10mL). Solid Pd/C (5% by wt) (0.030 g) was added and the reaction wasplaced under a balloon of hydrogen for 20 minutes. Catalyst was filteredoff using a 40 micron syringe filter. The solvent was removed by rotaryevaporation. The residue was taken up in DCM and loaded onto a silicagel column. The intermediate 20 was eluted with a 0 to 50% EtOAc inhexanes gradient. (Yield˜40 mg, 0.121 mmol, 73%).

¹H-NMR (CD₃CN, 300 MHz): δ 1.45 (m, 11H), 1.64 (m, 2H), 1.87 (m, 1H),2.25 (s, 3H), 2.38 (d, 1H), 2.51 (s, 3H), 2.95 (t, 1H), 4.02 (d, 1H),5.55 (d, 1H), 6.25 (s, 1H), 8.41 (s, 1H)

Example 20 Preparation of Intermediate 21

To a solution of the pyrazole intermediate 4 (0.5 g, 2.2 mmol) in aceticacid (5 ml) was added 3-methylpentane-2,4-dione (0.25 g, 2.2 mmol) andthe solution stirred at 90° C. for 30 min. Volatiles were removed underreduced pressure at 40° C., and the resulting residue was purified bysilica gel column (DCM/MeOH, gradient from 0% to 10%) to afford theproduct intermediate 21 (0.353 g, 47%) as a viscous oil.

¹H-NMR (DMSO, 400 MHz): δ 6.31 (s 1H), 5.58 (s 1H), 4.06 (d, J=12.8,1H), 2.92 (m 1H), 2.79 (m 3H), 2.58 (s, 3H), 2.52 (m 1H), 2.30 (s 3H),1.91 (m 1H), 1.57-1.40 (m, 12H).

LCMS m/z [M+H]⁺ C₁₉H₂₈N₄O₂ requires: 344.45. Found 345.20

HPLC Tr (min), purity %: 5.96, 95%.

Example 21 Preparation of Intermediate 22

Intermediate 21 (56 mg, 0.16 mmol) was dissolved in 1,4-dioxane (2 mL)and to the solution was added concentrated HCl (0.5 mL). The reactionmixture was stirred at room temperature for 1 h and then the solvent wasevaporated. The residue, intermediate 22 was used without furtherpurification.

Example 22 Preparation of Intermediate 23

The intermediate 19 (0.110 g, 0.301 mmol), was dissolved in 1,4-dioxane5 ml. Methyl amine (40% in water) (2 mL) was added and the reaction wasstirred for 2 hr. Solvents were removed by rotary evaporation. Theresidue was taken up in DCM and loaded onto a silica gel column.Intermediate 23 was eluted with a 0 to 80% EtOAc in hexanes gradient (98mg, 0.272 mmol, 90%).

¹H-NMR (CD₃CN, 300 MHz): δ 1.45 (m, 11H), 1.60 (m, 2H), 1.82 (m, 1H),2.30 (s, 3H), 2.40 (m, 1H, 2.42 (s, 3H), 2.95 (t, 1H), 3.35 (d, 3H),4.01 (d, 1H), 5.49 (m, 1H), 6.00 (s, 1H), 6.29 (bs, 1H).

Example 23 Preparation of Intermediate 24

The intermediate 23 (0.10 g, 0.28 mmol), was dissolved in anhydrous1,4-dioxane (6 ml). With stirring under nitrogen 4N HCl in dioxane (3ml) was added via syringe. The reaction was stirred for 2 hours at roomtemperature while monitoring by LC/MS. When the reaction was completethe solvent was removed by rotary evaporation. The product, intermediate24, was taken forward without further purification after it wascharacterized by LC/MS (Yield˜73 mg, 0.28 mmol, 100%).

LCMS m/z [M+H]⁺ 261

Example 24 Preparation of Intermediate 25

To a solution of the pyrazole intermediate 4 (3.22 g, 12.08 mmol) inacetic acid (25 ml) was added 1-cyclopropyl-1,3-butanedione (2.28 g,18.13 mmol) and the solution was stirred at 120° C. for 30 min. Thevolatiles were removed under reduced pressure at 40° C., and theresulting residue was purified by silica gel column (hexane/EtOAc,gradient from 0% to 50%) to afford intermediate 25 (1.72 g, 26%).

¹H-NMR (CDCl₃, 400 MHz): δ 6.44 (s 1H), 6.28 (s 1H), 5.58 (s, 1H),4.13-4.04 (m, 1H), 2.96-2.92 (m, 1H), 2.67 (s, 3H), 2.46-2.42 (m, 1H),2.14-1.85 (m, 4H), 1.47 (s, 9H), 1.13-1.02 (m, 6H).

LCMS m/z [M+H]⁺ C₂₀H₂₈N₄O₂ requires: 357.46. Found 357.13

Example 25 Preparation of Intermediate 26

Intermediate 25 (0.60 g, 1.68 mmol), was dissolved in anhydrous1,4-dioxane (6 ml). With stirring under nitrogen 4N HCl in dioxane (3ml) was added via syringe. The reaction was stirred for 2 hours at roomtemperature while monitoring by LC/MS. When the reaction was completesolvent was removed by rotary evaporation. The product, intermediate 26was taken forward without further purification (Yield 0.55 g, 100%).

¹H-NMR (CH₃OD, 400 MHz): δ 6.95 (d, J=1.2 Hz, 1H), 6.73 (s, 1H), 4.64(d, J=12 Hz, 1H), H), 3.52-3.51 (m, 1H), 3.23-3.20 (m, 1H), 2.86 (s 3H),2.40-2.02 (m, 2H), 2.26-1.81 (m, 5H), 1.41-1.30 (m, 4H).

LCMS m/z [M+H]⁺ C₁₅H₂₀N₄ requires: 257.35. Found 257.15

HPLC Tr (min), purity %: 1.65, 98%.

Example 26 Preparation of Intermediate 27

Intermediate 4 (10 g, 37.5 mmol) was dissolved in anhydrous DMF (60 mL).Ethyl 3-ethoxy-2-butenoate (11 g, 67.5 mmol) and cesium carbonate (18 g,56.3 mmol) were added. The reaction was stirred at 110° C. for 48 h andcooled to room temperature. The reaction was diluted with ethyl acetateand washed with saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution. The organic extract wasdried over anhydrous sodium sulfate and then concentrated under reducedpressure. The crude material was purified with silica gel column (0-80%EtOAc in hexanes) to give intermediate 27 (9.55 g, 77% yield).

¹H NMR (400 MHz, CD₃OD): δ 5.86 (s, 1H), 5.73 (s, 1H), 5.40 (m, 1H),4.00 (m, 1H), 2.91 (m, 1H), 2.54 (s, 3H), 2.36 (m, 1H), 1.80 (m, 1H),1.63 (m, 2H), 1.58-1.45 (m, 11H).

LC/MS (m/z): 333.1 [M+H]⁺

Example 27 Preparation of Intermediate 28

Intermediate 27(S)-tert-butyl-2-(7-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carboxylate (100 mg, 0.3 mmol) with POCl₃ (1 mL) were mixedand stirred at 110° C. for 1 h. The material was concentrated underreduced pressure and then dissolved in acetonitrile and a small amountof MeOH was added. The reaction was stirred at 0° C. for 30 min. Thesolid was collected and dried under high vacuum.

5-Chloro-2-(methylsulfonamido)benzoic acid (47 mg, 0.187 mmol) with HATU(71 mg, 0.187 mmol) were mixed and dissolved in anhydrous DMF (1 mL) andstirred for 1 h. The amine hydrogen chloride (49 mg, 0.17 mmol) wasdissolved in in anhydrous DMF (1 mL) and added to the reaction TEA (71uL, 0.51 mmol) was added and the material was stirred for 16 hrs. Thereaction material was diluted with ethyl acetate and washed withsaturated aqueous sodium chloride solution twice. The organic extractwas dried over anhydrous sodium sulfate and then concentrated underreduced pressure and purified with silica gel column (0-50% EtOAc inhexanes) to give intermediate 28 (57 mg, 39% yield).

LC/MS (m/z): 482.2 [M+H]⁺

Example 28 Preparation of Intermediate 29

Intermediate 4 (3 g, 0.02 mol) was dissolved in MeOH (30 ml), to thesolution was added dimethyl malonate (2.6 ml, 0.02 mmol) and 10% NaOMein MeOH (25 ml, 0.1 mmol). The reaction mixture was heated at 78° C. for5 h. Solvent was evaporated, the residue was redissolved in EtOAc (20mL), HOAc was added to make the solution slightly acidic, washed withbrine, organic solvent was evaporated, the residue was purified bysilica gel column chromatography to afford intermediate 29 (3 g, 78%).

LCMS m/z [M+H]⁺ C₁₆H₂₂N₄O₄ requires: 335.16. Found 335.05

HPLC Tr (min), purity %: 2.82, 98%

Example 29 Preparation of Intermediate 30

Intermediate 29 (10 g) was added to neat POCl₃ (25 ml), the reactionmixture was heated at 100° C. for 3 h. The solvent was evaporated and tothe residue was added MeOH until no bubble formed. Then, 30 mL ofacetonitrile was added to the above residue and orange solidprecipitated out of mixture to afford intermediate 30 (7.4 g, 92%).

LCMS m/z [M+H]⁺ C₁₁H₁₂N₄Cl₂ requires: 271.04. Found 271.07

HPLC Tr (min), purity %: 1.78, 98%

Example 30 Preparation of Intermediate 31

Intermediate 30 (4.2 g, 15.5 mmol) was added to CH₃CN (40 ml) and H₂O(40 ml), to the above mixture was added NaHCO₃ (2.6 G, 31 mmol) andmorpholine (1.35 g, 15.5 mmol). The reaction mixture was stirred at roomtemperature for 30 mins, solvents were evaporated and to the residue wasadded 20 ml of DCM, the mixture was filtered and filtrate was evaporatedto give intermediate 31 (4.5 g, 91%).

LCMS m/z [M+H]⁺ C₁₅H₂₀ClN₅O requires: 322.14. Found 322.10

HPLC Tr (min), purity %: 1.81, 98%

Example 31 Preparation of Intermediate 32

The 5-chloro-2-(methylsulfonamido)benzoic acid (5 g, 19.94 mmol) andHATU (9.5, 24.92 mmol) were dissolved in anhydrous DMF (50 ml). Afteractivation for 1 hour, to the above solution was added intermediate 31(4 g, 12.46 mmol) and triethylamine (6.93 ml). The reaction was stirredunder nitrogen for 2 hours. The solvents were removed by rotaryevaporation. The residue was purified with silica gel columnchromatography to provide intermediate 32. (Yield 4.7 g, 68%).

LCMS m/z [M+H]⁺ C₂₃H₂₆Cl₂N₆O₄S requires: 553.11. Found 553.16

HPLC Tr (min), purity %: 2.72, 98%

Example 32 Preparation of Intermediate 33

To a suspension of (5-chloro-2-(methylsulfonamido)benzoic acid) (0.7 g,2.8 mmol) in DCM (6 ml) was added oxalylchloride (2 M in DCM, 6 ml, 12mmol) and DMF (5 microliter) and the stirred for 3 h at roomtemperature. Volatiles were removed under vacuum and the residuedissolved in DCM (20 ml). With ice-water bath cooling, the amineintermediate 30 (0.78 g, 2.54 mmol) and ET₃N (0.55 g) was added andstirred for 10 min, then 30 min at room temperature. The reactionmixture was diluted with DCM (100 ml) and washed 3× with water.Volatiles were remove and the residue purified on silica gel(hexane/AcOEt=1/1). The product, intermediate 33, was obtained as acolorless oil in 75% purity and used without further purification in thenext step.

Example 33 Preparation of Intermediate 34

Intermediate 4 (5 g, 0.02 mol) in HOAc (20 mL) was treated with3-cyclopropyl-3-oxopropanoic acid methyl ester (14 g, 0.1 mmol) and themixture was stirred overnight at 100° C. The mixture was concentratedand purified via SiO₂ column chromatography (40 g SiO₂ Combiflash HPGold Column, 0-100% EtOAc/hexanes gradient) to afford intermediate 34 (4g, 83%).

LCMS m/z [M+H]⁺ C₁₉H₂₆N₄O₃ requires: 359.20. Found 359.10

HPLC Tr (min), purity %: 2.45, 98%

Example 34 Preparation of Intermediate 35

Starting material intermediate 34 (400 mg, 1.1 mol) was dissolved inlutidine (5 ml), to the mixture was added POCl₃ (340 mg, 2.2 mmol) andthe mixture was heated at 140° C. The reaction was completed in 30 mins.The mixture was concentrated and purified via SiO₂ column chromatography(40 g SiO₂ Combiflash HP Gold Column, 0-100% EtOAc/hexanes gradient) toafford intermediate 35 (388 mg, 92%).

LCMS m/z [M+H]⁺ C₁₉H₂₅ClN₄O₂ requires: 377.17. Found 377.11

HPLC Tr (min), purity %: 3.21, 98%

Example 35 Preparation of Intermediate 36

Starting material intermediate 35 (400 mg, 1.1 mmol) was dissolved inEtOH (10 ml), to the mixture was added 5% Pd on carbon (20 mg, 0.053mmol) and Et₃N (0.5 ml). The mixture was heated under hydrogen balloonat room temperature for 1.5 h. The mixture was filtered and filtrate wasconcentrated and purified via SiO₂ column chromatography to affordintermediate 36 (283 mg, 80%).

LCMS m/z [M+H]⁺ C₁₉H₂₆N₄O₂ requires: 343.21. Found 343.13

HPLC Tr (min), purity %: 2.93, 98%

Example 36 Preparation of Intermediate 37

Starting material intermediate 35 (200 mg, 0.55 mmol) was dissolved inmorpholine (10 ml), the mixture was stirred at room temperature for 30mins. The mixture was concentrated and purified via SiO₂ columnchromatography to afford intermediate 37 (200 mg, 88%).

LCMS m/z [M+H]⁺ C₂₃H₃₃N₅O₃ requires: 428.26. Found 428.17

HPLC Tr (min), purity %: 2.90, 98%

Example 37 Preparation of Intermediate 38

Following the procedure for the synthesis of compound 32, beginning withintermediate 115 (54 mg, 0.255 mmol) and tert-butyl(S)-1-(6-methyl-2-((S)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-ylcarbamate(intermediate 12 (79 mg, 0.198 mmol), intermediate 38 was synthesized asa white solid (107 mg, 90%) after silica gel column chromatography(15-75% ethyl acetate in hexanes).

Example 38 Preparation of Intermediate 39

Triphenylphosphine (87 mg, 0.332 mmol) was added to a solution ofintermediate 38 (97 mg, 0.163 mmol) in 5 mL of THF at room temperature.After 90 minutes, 0.2 mL of water was added and mixture was heated at60° C. overnight. The reaction mixture was concentrated under reducedpressure and purified by silica gel column chromatography (0-10%methanol in dichloromethane) to yield intermediate 39 (44 mg, 48%).

Example 39 Preparation of Intermediate 40

Intermediate 27 (1.68 g, 5 mmol) was dissolved in 4N HCl in dioxane (5mL) and stirred for 1 h. The material was concentrated under reducedpressure and dried under high vacuum to give solid which was then mixedwith THF (10 mL) and TEA (2.1 mL, 15 mmol). Cbz-Cl (739 uL, 5.25 mmol)was added dropwise and stirred for 1 h. The material was diluted withethyl acetate and washed with saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution. The organicextract was over anhydrous sodium sulfate and then concentrated underreduced pressure. The material was purified with silica gel column(0-80% EtOAc in hexanes) to give intermediate 40 (929 mg, 51% yield).

¹H NMR (400 MHz, CD₃OD): δ 7.31 (m, 5H), 5.85 (s, 1H), 5.74 (s, 1H),5.47 (m, 1H), 5.20-5.10 (m, 2H), 4.08 (m, 1H), 3.05 (m, 1H), 2.50 (s,3H), 2.34 (m, 1H), 1.85 (m, 1H), 1.63-1.51 (m, 4H).

LC/MS (m/z): 367.2 [M+H]⁺

Example 40 Preparation of Intermediate 41

Intermediate 40 (848 mg, 2.3 mmol) was mixed with toluene (7 mL). POCl₃(635 uL, 6.94 mmol) was added and stirred at 110° C. for 1.5 h. Thematerial was concentrated under reduced pressure. The material wasdissolved with ethyl acetate and washed with saturated aqueous sodiumbicarbonate solution twice and saturated aqueous sodium chloridesolution. The organic extract was dried over anhydrous sodium sulfateand then concentrated under reduced pressure. The material was purifiedwith silica gel column (0-30% EtOAc in hexanes) to give intermediate 41(425 mg, 48% yield).

¹H NMR (400 MHz, CD₃OD): δ 7.29 (m, 5H), 6.88 (s, 1H), 6.40 (s, 1H),5.64 (m, 1H), 5.21-5.10 (m, 2H), 4.12 (m, 1H), 3.08 (m, 1H), 2.68 (s,3H), 2.41 (m, 1H), 1.94 (m, 1H), 1.67-1.49 (m, 4H).

LC/MS (m/z): 385.0 [M+H]⁺

Example 41 Preparation of Intermediate 42

To a solution of intermediate 14 (100 mg, 0.18 mmol) in pyridine (2.00mL) was added N,N-dimethylsulfamoyl chloride (258 mg, 0.19 mmol) andtriethylamine (500 μL, 3.6 mmol), and the reaction mixture was stirredat 90° C. overnight. Then the reaction mixture was allowed to cool toroom temperature and was concentrated under reduced pressure. The cruderesidue was purified by combi-flash column chromatography (0-100%EtOAc/Hexane) to afford intermediate 42 (20 mg, 17%).

LCMS (m/z) 661.09 [M+H]⁺

MW 660.26

Example 42 Preparation of Intermediate 43

N-chlorosuccinimide (239 mg, 1.79 mmol) was added to a solution of4-fluoro-2-(methylsulfonamido)benzoic acid (351 mg, 1.51 mmol) in 9 mLof DMF at room temperature. After stirring overnight, mixture was pouredinto 90 mL of water and extracted three times with ethyl acetate. Thecombined organics were washed with water and brine, dried (MgSO₄),filtered, and concentrated under reduced pressure to yield intermediate43 (384 mg, 95%) as a 5:1 mixture of5-chloro-4-fluoro-2-(methylsulfonamido)benzoic acid to3-chloro-4-fluoro-2-(methylsulfonamido)benzoic acid, which was usedwithout further purification.

LCMS m/z [M+H]⁻ C₈H₇ClFNO₄S requires: 265.98. Found 266.07.

Example 43 Preparation of Intermediate 44

Intermediate 30 (1 g, 3.7 mmol) was dissolved in MeOH (5 ml) and to thesolution was added 1-N-Boc-piperazine (0.83 g, 4.4 mmol). The reactionmixture was stirred at room temperature for 10 mins. The solvent wasevaporated with reduced pressure and the residue was purified withcombi-flash column chromatography (0-50% MeOH/DCM) to affordintermediate 44 (1.7 g, 100%).

LCMS (m/z) 421.05 [M+H]⁺

MW 420.20

Example 44 Preparation of Intermediate 45

Intermediate 44 (800 mg, 1.9 mmol) was dissolved in MeOH (3 ml) and tothe solution was added azetidine (1 g, 19 mmol). The reaction mixturewas heated at 70° C. overnight. The solvent was evaporated with reducedpressure and the residue was purified with combi-flash columnchromatography (0-60% MeOH/DCM) to afford intermediate 45 (0.54 g, 65%).

LCMS (m/z) 442.39 [M+H]⁺

MW 441.57

Example 45 Preparation of Intermediate 46

2-Amino-5-chlorobenzoic acid (340 mg, 1.96 mmol) and HATU (930 mg, 2.44mmol) were dissolved in DMF (3 ml). The reaction mixture was stirred atroom temperature for 10 mins. To the above solution was addedintermediate 45 (500 mg, 1.22 mmol) and NEt₃ (680 μl). The reaction wasstirred at room temperature for 30 mins and was quenched with brine (10ml) and then extracted with EtOAc (20 ml). The organic layer was washedwith brine twice (10 ml) and then was evaporated under reduced pressure.The residue was purified with combi-flash column chromatography (0-100%EtOAc/Hexane) to afford intermediate 46 (0.5 g, 75%).

LCMS (m/z) 595.28 [M+H]⁺

MW 594.14

Example 46 Preparation of Intermediate 47

Intermediate 33 (50 mg, 0.1 mmol) was dissolved in THF (2 mL), to thesolution was added (S)-3-(Boc-amino)piperidine (22 mg, 0.11 mmol) andNEt₃ (27 μl). The reaction mixture was stirred at room temperatureovernight. The solvent was removed under reduced pressure and theresidue was purified with combi-flash column chromatography (0-50%MeOH/DCM) to afford intermediate 47 (29 mg, 44%).

Example 47 Preparation of Intermediate 48

3-(5-Amino-1H-pyrazol-3-yl)-morpholine-4-carboxylic acid tert-butylester and intermediate 4 (100 mg, 0.37 mmol) were dissolved in HOAc (2ml) and 3-cyclopropyl-2-methyl-3-oxo-propionic acid ethyl ester (0.24ml, 1.88 mmol) was added. The material was stirred at reflux for 1 hourand concentrated under reduced pressure. The material was diluted withethyl acetate and washed with saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution. The organicextract was dried over anhydrous sodium sulfate and then concentratedunder reduced pressure. The material was purified with Combiflash silicagel column (linear gradient from 0-80% MeOH in DCM) to yieldintermediate 48 (78 mg, 71%).

LCMS (m/z) 273.25 [M+H]⁺

MW 272.16

Example 48 Preparation of Intermediate 49

To a solution of 5-methyl-2-(methylsulfonyl)aminobenzoic acid (12) mg,0.55 mmol) in DMF (3 ml) was added HATU (281 mg, 0.74 mmol) and stirredfor 20 mins at room temperature. To the above solution was addedintermediate 48 in DMF (1 ml) followed by addition of TEA (0.1 ml). Thereaction was stirred at room temperature for 1 h. Diluted with ethylacetate and washed with saturated aqueous sodium chloride solution.Dried organic extract over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The residue was purified with PrepHPLC to yield intermediate 49 (110 mg, 62%).

LCMS (m/z) 474.23 [M+H]⁺

MW 483.19

Example 49 Preparation of Intermediate 50

Intermediate 49 (30 mg, 0.06 mmol) with POCl₃ (30 uL) was mixed inlutidine (2 mL) and stirred at 100° C. for 3 h and then concentratedunder reduced pressure. The material was dissolved in DCM and purifiedwith Combiflash silica gel column (linear gradient from 0-80% EtOAc inhexane) to yield intermediate 50 (15 mg, 48%).

LCMS (m/z) 502.10 [M+H]⁺

MW 501.03

Example 50 Preparation of Intermediate 51

Intermediate 19 (200 mg, 0.55 mmol) was dissolved in azetidine (1 ml)and the reaction mixture was heated to 60° C. for 30 min. The solventwas evaporated and the residue was redissolved in 1,4-dioxane and 4N HCl(1 ml) was added to the above solution. The reaction mixture was stirredat room temperature for 2 h. The solvent was removed under reducedpressure and the residue was purified with prep HPLC (0-100% CH₃CN/H₂O)to afford intermediate 51 (144 mg, 92%).

LCMS (m/z) 286.21 [M+H]⁺

MW 285

Example 51 Preparation of Intermediate 52

A solution of tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (955 mg,5.64 mmol) in 7 mL of DMSO and 0.3 mL of water was cooled to 0° C. NBS(1.51 g, 8.44 mmol) was added slowly over eight minutes and thenreaction mixture was warmed to room temperature. After four hours, themixture was poured into 100 mL of ice water and extracted with ethylacetate (2×70 mL). The combined organics were washed with 100 mL ofwater and 100 mL of brine, then dried (MgSO₄), filtered, andconcentrated under reduced pressure to yield intermediate 52 (1.48 g,99%) as a yellow film, which was used in the next step without furtherpurification.

¹H NMR (CDCl₃, 400 MHz): δ 4.46 (m, 1H), 4.15 (m, 1H), 4.02 (dd, J=5.2Hz, 13 Hz), 3.81 (m, 2H), 3.40 (m, 1H), 1.46 (s, 9H)

Example 52 Preparation of Intermediate 53

To a solution of intermediate 52 (467 mg, 1.75 mmol) in 7 mL of methanolat 0° C., was slowly added a 1.0 N aqueous solution of NaOH (2.4 mL, 2.4mmol). The reaction mixture was warmed to room temperature and stirredovernight. Methanol was then concentrated under reduced pressure and 20mL of water was added. The aqueous was extracted with ethyl acetate(3×25 mL) and combined organics were washed with 50 mL of brine, thendried (MgSO₄), filtered, and concentrated under reduced pressure toyield intermediate 53 (1.48 g, 99%) as a colorless oil, which was usedin the next step without further purification.

¹H NMR (CDCl₃, 400 MHz): δ 3.80 (d, J=12.8 Hz, 1H), 3.73 (d, J=12.8 Hz),3.65 (d, J=3.2 Hz, 2H), 3.31 (d, J=4.8 Hz, 1H), 3.28 (d, J=4.8 Hz, 1H),1.43 (s, 9H)

Example 53 Preparation of Intermediate 54

A solution of diethylaluminum cyanide in toluene (1.0 M, 3.3 mL, 3.3mmol) was added slowly to a solution of intermediate 53 (298 mg, 1.61mmol) in 9 mL of toluene at room temperature. After stirring overnight,the reaction mixture was quenched carefully (caution: exothermic) byslow addition of 1.0 N solution of NaOH_((aq)) and then diluted with 15mL of water. The aqueous was extracted with ethyl acetate (2×60 mL) andthe combined organics were washed with water (2×60 mL) and 60 mL ofbrine, then dried (MgSO₄), filtered, and concentrated under reducedpressure to yield intermediate 54 (314 mg, 85%) as a light yellow oil,which was used without further purification.

¹H NMR (CDCl₃, 400 MHz): δ 4.63 (m, 1H), 3.80-3.61 (m, 3H), 3.36 (m,1H), 3.05 (m, 1H), 2.64 (br s, 1H), 1.47 (s, 9H)

Example 54 Preparation of Intermediate 55

Intermediate 4 (266 mg, 1 mmol) was dissolved in acetonitrile (5 mL).Ethyl acetimidate hydrochloride (247 mg, 2 mmol) was then added followedby dropwise addition of acetic acid (57 μL, 1 mmol). Ethanol (1 mL) wasadded and the reaction mixture was stirred for 48 h. The resulting solidwas filtered and washed with acetonitrile. Filtrate was concentratedunder reduced pressure and purified with prep HPLC (5-95% Acetonitrilein water, 0.1% acetic acid buffer) to give intermediate 55 (185 mg,60%).

¹H NMR (400 MHz, CD₃OD): δ 5.93 (s, 1H), 5.45 (m, 1H), 4.05 (m, 1H),2.78 (m, 1H), 2.40 (s, 3H), 2.18 (m, 1H), 1.78 (m, 1H), 1.70-1.60 (m,2H), 1.47 (m, 12H).

LC/MS (m/z): 308.1 [M+H]⁺

Example 55 Preparation of Intermediate 56

Intermediate 55 (31 mg, 0.1 mmol) was mixed with xylenes (2 mL).Triethyl orthoacetate (60 μL, 0.33 mmol) was added and reaction mixturewas stirred at 120° C. for 24 h. After cooling to room temperature,mixture was concentrated under reduced pressure and purified with silicagel column chromatography (40% EtOAc in hexanes) to give intermediate 56(16 mg, 48%).

¹H NMR (400 MHz, CD₃OD): δ 6.30 (s, 1H), 5.54 (m, 1H), 4.04 (m, 1H),2.95 (m, 1H), 2.87 (s, 3H), 2.58 (s, 3H), 2.47 (m, 1H), 1.89 (m, 1H),1.65 (m, 2H), 1.47 (m, 12H).

LC/MS (m/z): 332.1 [M+H]⁺

Example 56 Preparation of Intermediate 57

A solution of intermediate 2 (1.52 g, 6.26 mmol) in 15 mL of anhydrousTHF was cooled to −78° C. under argon. A solution of Tebbe Reagent (0.5M in toluene, 15 mL, 7.5 mmol) was added dropwise and reaction mixturestirred at −78° C. for one hour and was then warmed to room temperature.After two hours, reaction mixture was placed in a dropping funnel andthen added dropwise to a 500 mL round bottom flask containing a stirringsolution of 1N NaOH_((aq)) at 0° C. After complete addition, 75 mL ofethyl acetate was added and mixture was stirred vigorously overnight(yellow precipitate). Mixture was then filtered over a medium frit andfiltrate was added to a separatory funnel. After separating the aqueouslayer, the remaining organic layer was washed with brine (2×125 mL),dried (Na₂SO₄), filtered and concentrated under reduced pressure leavinga yellow oily residue. Hexane was added to crash out more solid andmixture was filtered. Filtrate was concentrated and remaining residuewas purified via silica gel column chromatography (0-25% ethyl acetatein hexanes) to yield intermediate 57 (332 mg, 22%) as a clear oil.

¹H-NMR (CDCl₃, 400 MHz): δ 4.74 (m, 1H), 4.06 (m, 1H), 3.95 (m, 1H),3.91 (m, 1H), 3.54 (s, 3H), 2.91 (m, 1H), 2.07 (m, 1H), 1.65-1.50 (m,3H), 1.47 (s, 9H), 1.45-1.32 (m, 2H).

Example 57 Preparation of Intermediate 58

NBS (339 mg, 1.89 mmol) was added slowly to a solution of intermediate57 (454 mg, 1.88 mmol) in 10 mL of THF and 3 mL of water at roomtemperature. After 25 minutes, reaction mixture was poured into 45 mL ofsaturated NaHCO_(3(aq)). Aqueous was extracted with ethyl acetate (3×30mL). Combined organics were washed with 75 mL of brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. Resulting residue waspurified via silica gel column chromatography (5-20% ethyl acetate inhexanes) to yield intermediate 58 (219 mg, 40%) as a clear oil.

¹H-NMR (CDCl₃, 400 MHz): δ 4.89 (m, 1H), 4.03 (s, 2H), 3.05-2.75 (m,1H), 2.14 (m, 1H), 1.75-1.61 (m, 3H), 1.47 (s, 9H), 1.44-1.33 (m, 2H).

Example 58 Preparation of Intermediate 59

A mixture of intermediate 58 (73 mg, 0.238 mmol), NaHCO₃ (41 mg, 0.488mmol), and 2,4-dimethyl-6-aminopyridine (60 mg, 0.491 mmol) in 3 mL ofethanol was heated at reflux overnight. After cooling to roomtemperature the reaction mixture was concentrated under reduced pressureand purified by prep HPLC (15-100% acetonitrile (with 0.1%trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) toyield intermediate 59 (6.0 mg, 7.6%) as a solid, trifluoroacetic acidsalt, after lyophilization.

LCMS m/z [M+H]⁺ C₁₉H₂₇N₃O₂ requires: 330.21. Found 330.38.

Example 59 Preparation of Intermediate 60

A solution of collidine (1 g, 8.25 mmol) in THF (5 mL) was cooled to−78° C. and BuLi (5.15 mL, 1.6 M in hexanes) was added dropwise. A darkred color formed immediately. The solution was stirred for 10 minutes at−78° C. Intermediate 2 (0.5 g, 0.2 mmol) in THF (5 mL) was addeddropwise and stirred at −78° C. for 15 minutes. The solution wasquenched with acetic acid (0.5 mL) in THF (2 mL) and warmed to roomtemperature. The volatiles were partially removed under reduced pressureand EtOAc (50 mL) was added. The organic layer was washed with brine(2×50 mL), dried, and concentrated under reduced pressure. Silica gelcolumn chromatography (0-60% EtOAc in hexanes) afforded intermediate 60as a colorless oil (1.36 g, 91%).

LCMS m/z [M+H]⁺ 332.99.

HPLC Tr (min), purity %: 2.34, 60%

Example 60 Preparation of Intermediate 61

Intermediate 60 (1.3 g, 3.91 mmol), hydroxylamine (1.35 g, 19.5 mmol)and NaOAc (1.92 g, 23.46 mmol) were stirred at reflux in EtOH (20 mL)for 1 h. The volatiles were partially removed under reduced pressure.EtOAc (50 mL) was added and the organic layer was washed with brine(2×50 mL), dried, and concentrated under reduced pressure. The compoundwas purified by silica gel column chromatography (0-60% EtOAc inhexanes) to afford intermediate 61 as a colorless oil (1.10 g, 81%).

LCMS m/z [M+H]⁺ 348.04

HPLC Tr (min), purity %: 2.28, 80%

Example 61 Preparation of Intermediate 62

Intermediate 61 (0.348 g, 1.0 mmol) andO-(2,4-dinitro-phenyl)-hydroxylamine (0.239 g, 1.2 mmol) were stirred inMeCN under nitrogen for 16 h. Cs₂CO₃ (0.5 g) was added and thesuspension stirred at room temperature for 2 h. The volatiles wereremoved under reduced pressure and the residue was dissolved inMeCN/water and purified by preparatory HPLC (5-95% H₂O/MeCN, 0.1% TFA)to afford intermediate 62 as a colorless powder (0.119 g, 34%).

LCMS m/z [M+H]⁺ 329.95

HPLC Tr (min), purity %: 2.81, 98%

Example 62 Preparation of Intermediate 63

Intermediate 62 (0.119 g, 0.362 mmol) was stirred in dioxane (2 mL) andHCl (4 mL, 4 M in dioxane) was added at room temperature and stirred for1 h. The volatiles were removed under reduced pressure to afford the HClsalt of intermediate 63 as an off-white powder (0.125 g, >100%).

LCMS m/z [M+H]⁺ 230.16

¹H NMR (CDCl₃, 400 MHz): δ 9.44 (s, 2H), 7.36 (s, 1H), 6.73 (s, 1H),6.70 (s, 1H), 4.46 (m, 1H), 3.28 (d, 12.4 Hz, 1H), 3.04 (m, 1H), 2.62(s, 3H), 2.30 (s, 3H), 2.10 (d, 13.6 Hz), 1.93-1.78 (m, 4H), 1.66 (m,1H).

HPLC Tr (min), purity %: 1.34, 98%

Example 63 Preparation of Intermediate 64

A mixture of intermediate 58 (14 mg, 0.046 mmol) and6-chloropyridazin-3-amine (17 mg, 0.131 mmol) in 1.2 mL of ethanol washeated a reflux overnight. After cooling to room temperature thereaction mixture was concentrated under reduced pressure and purifiedvia silica gel column chromatography (5-50% ethyl acetate in hexanes) toyield intermediate 64 as a clear film (9 mg, 60%).

LCMS m/z [M+H]⁺ C₁₇H₂₂ClN₃O₂ requires: 337.14. Found 337.04.

Example 64 Preparation of Intermediate 65

Trifluoroacetic acid (0.070 mL, 0.831 mmol) was added to a solution ofintermediate 64 (8 mg, 0.024 mmol) in 1 mL of CH₂Cl₂. After stirringovernight, LC/MS indicated full removal of Boc group. The reactionmixture was concentrated under reduced pressure and dried in-vacuo fortwo hours. To a solution of the resulting residue dissolved in 1.5 mL ofanhydrous CH₂Cl₂ was added 5-chloro-2-(methylsulfonamido)benzoylchloride (6.5 mg, 0.0252 mmol). The mixture was cooled to 0° C.,triethylamine (7.0 μL, 0.049 mmol) was added, and the resulting mixturewas warmed to room temperature and stirred overnight. LC/MS monitoringindicated full conversion to intermediate 65 (11.5 mg, 99%). Thereaction mixture was concentrated under reduced pressure and usedwithout further purification.

LCMS m/z [M+H]⁺ C₁₉H₁₉Cl₂N₅O₃S requires: 468.06. Found 467.89.

Example 65 Preparation of Intermediate 66

A mixture of intermediate 58 (293 mg, 0.958 mmol) and6-chloro-5-methylpyridazin-3-amine (195 mg, 1.35 mmol) in 16 mL ofethanol was heated at 77° C. overnight. After cooling to roomtemperature the reaction mixture was concentrated under reduced pressureand the residue was purified via silica gel column chromatography(5-100% ethyl acetate in hexanes) to yield intermediate 66 (125 mg, 38%)as a white solid.

LCMS m/z [M+H]⁺ C17H₂₃ClN₄O₂ requires: 351.15. Found 351.12.

¹H-NMR (CDCl₃, 400 MHz): δ 7.76 (s, 1H), 7.62 (s, 1H), 5.57 (m, 1H),4.09 (m, 1H), 2.89 (m, 1H), 2.52 (m, 1H), 2.45 (s, 3H), 1.86 (m, 1H),1.70-1.30 (m, 4H), 1.47 (s, 9H).

Example 66 Preparation of Intermediate 67

Following the procedure for the synthesis of intermediate 65, beginningwith intermediate 66 (120 mg, 0.343 mmol), intermediate 67 (129 mg, 78%)was synthesized as a white solid.

LCMS m/z [M+H]⁺ C₂₀H₂₁Cl₂N₅O₃S requires: 482.07. Found 481.86.

¹H-NMR (CDCl₃, 400 MHz): δ 10.0 (s, 1H), 8.34 (s, 1H), 7.73-7.53 (m,2H), 7.37-7.30 (m, 1H), 6.27 (s, 1H), 3.31 (m, 1H), 2.95 (s, 3H), 2.46(s, 3H), 2.27 (m, 2H), 1.77 (m, 2H), 1.68-1.38 (m, 4H).

Example 67 Preparation of Intermediate 68

Triethylamine (0.35 mL, 2.51 mmol) was added to a mixture ofintermediate 67 (109 mg, 0.226 mmol) and (S)-tert-butylpyrrolidin-3-ylcarbamate (469 mg, 2.52 mmol) in 9 mL of anhydrousmethanol. The mixture was heated at 75° C. overnight. Analytical HPLCindicated about 15% conversion to intermediate 68. Additional(S)-tert-butyl pyrrolidin-3-ylcarbamate (1.81 g) was added along withtriethylamine (0.9 mL) and mixture was heated again for five days. Thereaction mixture was cooled to room temperature, concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (10-50% ethyl acetate in hexanes) to yieldintermediate 68 (91 mg, 64%) as a white solid.

LCMS m/z [M+H]⁺ C₂₉H₃₈ClN₇O₅S requires: 632.23. Found 632.55.

Example 68 Preparation of Intermediate 69

A mixture of 3,6-dichloro-4-methylpyridazine (333 mg, 2.04 mmol) in 3.3mL of 28% NH₄OH and 2 mL of ethanol was heated at 100° C. in a sealedtube for 48 hours. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The resulting solid waswashed with ether and decanted (5×) yielding a light yellow solid (123mg, 42%) as a 55/45 mixture of 6-chloro-5-methylpyridazin-3-amine andintermediate 69 by analytical HPLC.

LCMS m/z [M+H]⁺ C₅H₆ClN₃ requires: 144.03. Found 144.10.

Example 69 Preparation of Intermediate 70

A mixture of intermediate 58 (105 mg, 0.343 mmol) and the mixture of6-chloro-5-methylpyridazin-3-amine and intermediate 69 (75 mg, 0.521mmol) in 6 mL of ethanol was heated at 77° C. overnight. After coolingto room temperature, the reaction mixture was concentrated under reducedpressure and the residue was purified via silica gel columnchromatography (5-40% ethyl acetate in hexanes) to yield intermediate 70(7 mg, 6%) as the first eluting product followed by its isomer,intermediate 66 (17 mg, 14%).

Intermediate 70: LCMS m/z [M+H]⁺ C₁₇H₂₃ClN₄O₂ requires: 351.15. Found351.04.

Example 70 Preparation of Intermediate 72

Following the procedure for synthesis of intermediate 65, but beginningwith intermediate 70 (7 mg, 0.020 mmol), intermediate 72 was recoveredas a clear film (5.8 mg, 60%).

LCMS m/z [M+H]⁺ C₂₀H₂₁Cl₂N₅O₃S requires: 482.07. Found 481.94.

Example 71 Preparation of Intermediate 73

To a solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid(30.0 g, 130 mmol) in tetrahydrofuran (260 mL) was addedcarbonyldiimidazole (21.2 g, 130 mmol) at room temperature. After 18 h,the reaction mixture was concentrated under reduced pressure and thecrude residue was partitioned between ethyl acetate (600 mL) and water(200 mL). The phases were separated, and the organic layer was washedwith water (200 mL), with saturated aqueous sodium bicarbonate solution(200 mL), and with saturated sodium chloride solution (200 mL). Theorganic layer was dried over Na₂SO₄, and was concentrated under reducedpressure to afford intermediate 73 (36 g, 99%) as a white crystallinesolid.

¹H NMR (CDCl₃, 400 MHz): δ 8.21 (br s, 1H), 7.51 (br s, 1H), 7.08 (br s,1H), 5.45-5.01 (m, 1H), 3.92 (br d, J=13.6 Hz, 1H), 3.39-3.05 (m, 1H),2.13-1.98 (m, 1H), 1.96-1.82 (m, 1H), 1.78-1.56 (m, 2H), 1.55-1.30 (m,11H).

R_(f)=0.30 (50% ethyl acetate/hexanes).

Example 72 Preparation of Intermediate 74

To a solution of potassium 2-methylpropan-2-olate (14.5 g, 129 mmol) indimethylsulfoxide (129 mL) was added nitromethane (6.93 mL, 129 mmol) atroom temperature. After 1 h, a solution of intermediate 73 (36.0 g, 129mmol) in dimethylsulfoxide was added via cannula and the reactionmixture was stirred at room temperature. After 15 h, acetic acid (50 mL)was added and the resulting mixture was partitioned betweendichloromethane (400 mL) and water (1 L). The phases were separated, andthe aqueous layer was extracted with dichloromethane (3×400 mL). Thecombined organic layers were dried over Na₂SO₄, and were concentratedunder reduced pressure. The crude residue was purified via SiO₂ columnchromatography (330 g SiO₂ Combiflash HP Gold Column, 0-100% ethylacetate/hexanes) to afford intermediate 74 (35.2 g, 99%) as a yellowsolid.

¹H NMR (CDCl₃, 400 MHz): δ 5.36 (s, 2H), 4.73 (br s, 1H), 4.09-3.74 (m,1H), 3.04-2.69 (m, 1H), 2.14 (br d, J=10.6 Hz, 1H), 1.75-1.55 (m, 3H),1.54-1.39 (m, 11H).

LCMS (ESI) m/z 271.42 [M−H]⁻, t_(R)=2.48 min.

R_(f)=0.70 (50% ethyl acetate/hexanes.

Example 73 Preparation of Intermediate 75

To a suspension of palladium on carbon (10% wt, 78.0 mg, 73.0 μmol) inethanol (3.6 mL) was added intermediate 74 (400 mg, 1.47 mmol) at roomtemperature under an argon atmosphere. The reaction vessel was evacuatedand refilled with hydrogen gas (3×), and balloon filled with hydrogengas was appended to the vessel. The reaction mixture was stirredvigorously for 2 h at which point the reaction was filtered through apad of celite. To the filtrate was added 1H-pyrazole-1-carboximidamide(323 mg, 2.20 mmol) followed by sodium carbonate (233 mg, 2.20 mmol),and the resulting mixture was stirred at room temperature. After 16 h,the reaction mixture was partitioned between ethyl acetate (150 mL) andwater (150 mL). The phases were separated, and the aqueous layer wasextracted with ethyl acetate (2×150 mL). The combined organic layerswere dried over Na₂SO₄, and were concentrated under reduced pressure.The crude residue was purified via SiO₂ column chromatography (12 g SiO₂Combiflash HP Gold Column, 0-20% methanol/dichloromethane) to affordintermediate 75 (119 mg, 30%) as a yellow oil.

¹H NMR (CD₃OD, 400 MHz): δ 6.25 (s, 1H), 5.19 (d, J=4.9 Hz, 1H), 3.93(d, J=10.4 Hz, 1H), 2.91 (t, J=13.4 Hz, 1H), 2.13 (d, J=13.3 Hz, 1H),1.76-1.62 (m, 1H), 1.62-1.51 (m, 3H), 1.43 (s, 10H).

HPLC t_(R) (min), purity %: 2.83, 99%.

R_(f)=0.45 (20% methanol/dichloromethane).

Example 74 Preparation of Intermediate 76

To a solution of intermediate 75 (92 mg, 0.35 mmol), and dimethylmalonate (80 L, 0.70 mmol), in ethanol (1.7 mL) was added sodiumethoxide (21 wt % in ethanol, 225 mg, 0.70 mmol) at room temperatureunder an argon atmosphere and the resulting mixture was heated to 70° C.After 19 h, the reaction mixture was allowed to cool to room temperatureand acetic acid was added until the mixture was pH=7. The resultingmixture was purified by preparatory HPLC (5-100% MeCN/H₂O, 0.1%trifluoroacetic acid modifier) to afford intermediate 76 (80 mg, 69%) asa colorless oil.

¹H NMR (CD₃OD, 400 MHz): δ 7.26 (s, 1H), 7.08 (s, 1H), 5.44 (d, J=4.8Hz, 1H), 4.04 (d, J=14.0 Hz, 1H), 2.90 (t, J=13.1 Hz, 1H), 2.16 (d,J=14.0 Hz, 1H), 1.94-1.81 (m, 1H), 1.75-1.52 (m, 4H), 1.49 (s, 9H).

LCMS (ESI) m/z 335.14 [M+H]⁺, t_(R)=2.24 min.

Example 75 Preparation of Intermediate 77

Phosphoryl chloride (1 mL) was added to intermediate 76 (38 mg, 0.11mmol) at room temperature under an argon atmosphere and the resultingmixture was heated to 100° C. After 7 h, the reaction mixture wasallowed to cool to room temperature and was concentrated under reducedpressure. To the resulting residue was added azetidine hydrochloride(106 mg, 1.14 mmol), triethylamine (317 μL, 2.28 mmol), and methanol (2mL) at room temperature and the reaction mixture was heated to 70° C.After 16 h, the reaction mixture was allowed to cool to room temperatureand was purified by preparatory HPLC (5-100% MeCN/H₂O, 0.1%trifluoroacetic acid modifier) to afford intermediate 77 (20.2 mg, 56%)as an orange oil.

LCMS (ESI) m/z 313.13 [M+H]⁺, t_(R)=1.49 min.

Example 76 Preparation of Intermediate 78

Ethyl O-Mesityl sulfonyl acetohydroxanate (1 g, 3.5 mmol) and dioxane (3mL) were mixed under argon. The suspension was cooled to 0° C. and thentreated with HClO₄ (70% aqueous solution, 0.39 mL). After stirring at 0°C. for 30 minutes, ice-water (7 mL) was added to the reaction mixture.The white precipitate formed was filtered and washed with water,transferred to a round bottom flask while wet, and immediately dissolvedin DCM (30 mL). Trace amount of water was removed via separatory funneland the organic layer was dried over MgSO₄ and filtered. To the aboveDCM solution was then added a solution of 6-amino-2, 4-lutidine in DCM(2 mL) slowly at 0° C. The reaction mixture was then stirred at roomtemperature for 1 hour. To the reaction mixture was added tert-butylmethyl ether (5 mL). The white precipitate was filtered and washed withDCM/tert-butyl methyl ether (1/1, 40 mL) and dried in vacuo to yieldintermediate 78 (0.68 g, 58%).

LCMS m/z [M+H]⁺ C₇H₁₂N₃ requires: 138.19. Found 138.12

HPLC Tr (min), purity %: 0.39, 95%

Example 77 Preparation of Intermediate 79

Intermediate 78 (100 mg, 0.3 mmol) and(S)-2-formyl-piperidine-1-carboxylic acid tert-butyl ester (128 mg, 1.2mmol) were dissolved in DMF (2 mL). The reaction was heated overnight at90° C. and then triethylamine (0.17 mL, 1.2 mmol) was added. After 1 h,the reaction was diluted with ethyl acetate (20 mL) and washed withbrine (3×20 mL). Organic phase was evaporated under vacuum and theresidue was purified with silica gel column chromatography (0-100% ethylacetate in hexanes) to provide intermediate 79 (16 mg, 11%).

LCMS m/z [M+H]⁺ C₁₈H₂₆N₄O₂ requires: 330.42. Found 330.97

HPLC Tr (min), purity %: 2.40, 98%

Example 78 Preparation of Intermediate 80

A solution of 85% phosphoric acid in water (0.010 mL) was added to asolution of intermediate 79 (16 mg, 0.05 mmol) in DCM (0.2 mL). Afterstirring at room temperature for 10 minutes, the reaction mixture wasevaporated under reduced pressure and the residue was purified usingprep HPLC (0-100% acetonitrile in water) to provide intermediate 80 (9.6mg, 86%).

LCMS m/z [M+H]⁺ C₁₃H₁₈N₄ requires: 231.31. Found 231.08

HPLC Tr (min), purity %: 1.30, 98%

Example 79 Preparation of Intermediate 81

A mixture of 3chloro-6-methylpyridazine (1 g, 7.8 mmol) dissolved inazetidine (4.5 g, 78 mmol) was heated at 90° C. overnight. The reactionmixture was then evaporated under reduced pressure and the residue waspurified using silica gel column chromatography (0-10% methanol indichloromethane) to provide intermediate 81 (980 mg, 84%).

LCMS m/z [M+H]⁺ C₈H₁₁N₃ requires: 149.19. Found 149.08

HPLC Tr (min), purity %: 1.80, 98%

Example 80 Preparation of Intermediate 82

Intermediate 81 (387 mg, 2.6 mmol) and intermediate 58 (200 mg, 0.65mmol) were dissolved in CH₃CN (2 mL). The reaction was heated overnightat 90° C. and then 1,8-diazabicyclo-[5,4,0]undec-7-ene (0.19 mL, 1.3mmol) was added. After 1 h, the reaction was diluted with ethyl acetate(20 mL) and washed with brine (3×20 mL). The organic phase wasevaporated under reduced pressure and the residue was purified withsilica gel column chromatography (0-100% ethyl acetate in hexanes) toprovide intermediate 82 (14 mg, 4%).

LCMS m/z [M+H]⁺ C₂₀H₂₈N₄O₂ requires: 356.46. Found 356.94

HPLC Tr (min), purity %: 2.64, 98%

Example 81 Preparation of Intermediate 83

Intermediate 82 (14 mg, 0.04 mmol) was dissolved in DCM (0.2 mL) and asolution of 85% phosphoric acid in water (0.010 mL) was added. Afterstirring at room temperature for 10 minutes, the reaction mixture wasquenched with NaHCO₃ and extracted with EtOAc. The organic phase wasevaporated under reduced pressure and the residue was purified usingprep HPLC (0-100% acetonitrile in water) to provide intermediate 83 (10mg, 100%).

LCMS m/z [M+H]⁺ C₁₅H₂₀N₄ requires: 257.35. Found 257.13

HPLC Tr (min), purity %: 1.59, 98%.

Example 82 Preparation of Intermediate 84

(S)-(−)-1-(carbobenzyloxy)-2-piperidinecarboxylic acid (500 mg, 1.9mmol) and HATU (1.16 g, 3 mmol) were dissolved in anhydrous DMF (1 mL).After activation for 1 hour, 2,3-diamino-4,6-dimethylpyridine (253 mg,1.9 mmol) and triethylamine (0.53 mL, 3.80 mmol) were added. Thereaction mixture was stirred under nitrogen for 2 hours. The solventswere removed under reduced pressure and the residue was treated withacetic acid (2.5 mL) and heated at 170° C. The solvent was evaporatedunder reduced pressure and the residue was purified via silica gelcolumn chromatography (0-100% ethyl acetate in hexanes) to provideintermediate 84. (Yield 111 mg, 16%).

LCMS m/z [M+H]⁺ C₂₁H₂₄N₄O₂ requires: 365.19. Found 365.12

HPLC Tr (min), purity %: 2.47, 98%.

Example 83 Preparation of Intermediate 85

Intermediate 84 (43 mg, 0.118 mmol) was dissolved in EtOH (5 mL) underargon. To the solution was added Pd on carbon (40 mg) and the reactionmixture was stirred under an atmosphere of H₂ at room temperatureovernight. The mixture was filtered and the filtrate was concentratedunder reduced pressure. The remaining residue was purified with prepHPLC (0-100% acetonitrile in water) to provide intermediate 85 (27 mg,87%).

LCMS m/z [M+H]⁺ C₁₃H₁₈N₄ requires: 231.15. Found 231.07

HPLC Tr (min), purity %: 0.79, 98%

Example 84 Preparation of Intermediate 86

To a solution of hydrazinecarboximidamide hydrochloride (320 mg, 2.81mmol) in dimethylformamide (14 mL) was addedtert-butyl-2-formylpiperidine-1-carboxylate (600 mg, 2.81 mmol) at roomtemperature open to atmosphere. The resulting mixture was heated to 90°C. and stirred vigorously open to atmosphere. After 16 hours, thereaction mixture was allowed to cool to room temperature and was stirredvigorously open to atmosphere. After 2 days, acetylacetone (290 L, 2.81mmol) and cesium carbonate (915 mg, 2.81 mmol) were added and thereaction mixture was heated to 90° C. open to atmosphere. After 6 hours,the reaction was allowed to cool to room temperature and was partitionedbetween ethyl acetate (250 mL) and water (250 mL). The phases wereseparated, and the organic layer was washed with saturated sodiumchloride solution (3×100 mL). The organic layer was dried over Na₂SO₄,and was concentrated under reduced pressure. The crude residue waspurified via SiO₂ column chromatography (12 g SiO₂ Combiflash HP GoldColumn, 0-100% ethyl acetate/hexanes) to afford intermediate 86 (67.6mg, 7%) as a yellow oil.

LCMS (ESI) m/z 332.14 [M−H]⁻, t_(R)=2.38 min.

R_(f)=0.45 (ethyl acetate).

Example 85 Preparation of Intermediate 87

Trifluoroacetic acid (1 mL, 12.9 mmol) was added to a solution ofintermediate 66 (131 mg, 0.375 mmol) in 20 mL of dichloromethane at roomtemperature. After stirring overnight, the reaction mixture wasconcentrated under reduced pressure and dried in-vacuo for two hours.The resulting film was dissolved in 4 mL of methanol and (S)-tert-butylpyrrolidin-3-ylcarbamate (710 mg, 3.82 mmol) and triethylamine (0.52 mL,3.7 mmol) were added. Mixture was heated at 77° C. overnight. LC/MSindicated approximately 25% conversion to desired product. Further(S)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.9 mmol) was added andmixture stirred at 77° C. for 72 hours. After cooling to roomtemperature, the resulting residue was purified via silica gel columnchromatography (0-10% methanol in dichloromethane) to yield intermediate87 (135 mg, 90%) as an off-white film.

LCMS m/z [M+H]⁺ C₂₁H₃₂N₆O₂ requires: 401.26. Found 401.24.

Example 86 Preparation of Intermediate 88

HATU (48 mg, 0.126 mmol) was added to a solution of5-methyl-3-(methylsulfonamido)thiophene-2-carboxylic acid (24 mg, 0.102mmol) in 2 mL of anhydrous DMF at room temperature. After 90 minutes, a0.5 mL acetonitrile solution of intermediate 87 (36 mg, 0.09 mmol) wasadded, followed by triethylamine (0.030 mL, 0.217 mmol). After stirringovernight, the reaction mixture was poured into a 1:1 solution of waterand brine and extracted with ethyl acetate three times. The combinedorganics were washed with a 1:1 solution of water and brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas purified via silica gel column chromatography (5-100% ethyl acetatein hexanes) to yield intermediate 88 (22 mg, 40%) as a clear film.

LCMS m/z [M+H]⁺ C₂₈H₃₉N₇O₅S requires: 618.25. Found 618.28.

Example 87 Preparation of Intermediate 89

Following the procedure of intermediate 88, beginning with intermediate87 (38 mg, 0.095 mmol) and intermediate 95 (44 mg, 0.143 mmol),intermediate 89 (12 mg, 18%) was recovered a clear film.

LCMS m/z [M+H]⁺ C₃₀H₄₀BrN₇O₅S requires: 690.20. Found 690.21.

Example 88 Preparation of Intermediate 90

Trifluoroacetic acid (0.070 mL, 0.831 mmol) was added to a solution ofintermediate 64 (110 mg, 0.33 mmol) in 5 mL of CH₂Cl₂. After stirring atroom temperature overnight, the reaction mixture was concentrated underreduced pressure and the residue was purified by prep HPLC (15-100%Acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1%trifluoroacetic acid)) to yield intermediate 90 (114 mg, 100%) as asolid, trifluoroacetic acid salt, after lyophilization.

LCMS m/z [M+H]⁺ C₁₁H₁₃ClN₄ requires: 237.08. Found 237.10.

HPLC Tr (min), purity %: 1.36, 95%

Example 89 Preparation of Intermediate 91

HATU (45 mg, 0.12 mmol) and 6-Methyl-2-picolinic acid (12 mg, 0.09 mmol)were mixed in 2 mL of DMF and the reaction mixture was stirred for tenminutes before intermediate 90 (20 mg, 0.06 mmol) and triethylamine (33μL, 0.24 mmol) were added to the solution. The reaction mixture wasstirred for one hour at room temperature, was diluted with CH₃CN/H₂O(2/2 mL), and was then purified by prep HPLC (15-100% Acetonitrile (with0.1% trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) toyield intermediate 91 (12 mg, 63%) as a solid, trifluoroacetic acidsalt, after lyophilization.

LCMS m/z [M+H]⁺ C₁₈H₁₈ClN₅O requires: 356.12. Found 356.14.

HPLC Tr (min), purity %: 1.89, 98%

Example 90 Preparation of Intermediate 92

HATU (45 mg, 0.12 mmol) and 2-methyl-5-chlorobenzoic acid (16 mg, 0.09mmol) were mixed in 2 mL of DMF and the reaction mixture was stirred forten minutes before intermediate 90 (20 mg, 0.06 mmol) and triethylamine(33 μL, 0.24 mmol) were added to the solution. The reaction mixture wasstirred for 1 h at room temperature, was diluted with CH₃CN/H₂O (2/2mL), and was then purified by prep HPLC (15-100% acetonitrile (with 0.1%trifluoroacetic acid) in water (with 0.1% trifluoroacctic acid)) toyield intermediate 92 (14 mg, 64%) as a solid, trifluoroacetic acidsalt, after lyophilization.

LCMS m/z [M+H]⁺ C₁₉H₁₈Cl₂N₄O requires: 389.09. Found 389.13.

HPLC Tr (min), purity %: 2.34, 98%

Example 91 Preparation of Intermediate 93

A solution of (S)-tert-butyl 2-ethynylpiperidine-1-carboxylate (AnichemLLC, North Brunswick, N.J., USA) (100 mg, 0.48 mmol),2-bromo-4,6-dimethylpyridin-3-amine (96 mg, 0.48 mmol), CuI (4.3 mg,0.0225 mmol) and Pd(Cl)₂(PPh₃)₂ (16 mg, 0.025 mmol) in 5 mL oftriethylamine was stirred under nitrogen at 0° C. for 5 minutes followedby heating to 90° C. for 1 hour. After cooling to room temperature, thevolatiles were removed under reduce pressure and the crude product waspurified via silica gel column chromatography (0-60% ethyl acetate inhexanes) to afford intermediate 93 (78 mg, 49%) as a colorless oil.

LCMS m/z [M+H]⁺ 330.02.

HPLC Tr (min), purity %: 2.41, 95%

Example 92 Preparation of Intermediate 94

A solution of hydrogen chloride in dioxane (4N, 8 mL, 32 mmol) was addedto a mixture of intermediate 93 (429 mg, 1.3 mmol) in 10 mL of dioxane.After stirring for 1 hour, the volatiles were removed under reducedpressure and the resulting residue was freeze-dried from acetonitrileand water to afford intermediate 94 (366 mg, >100%) as an off-whitepowder, hydrochloric acid salt.

LCMS m/z [M+H]⁺ 229.97

HPLC Tr (min), purity %: 1.57, 95%

Example 93 Preparation of Intermediate 95

Methanesulfonyl chloride (0.7 mL, 9.14 mmol) was added slowly to amixture of 2-amino-2-(2-bromophenyl)acetic acid (660 mg, 2.87 mmol) in 8mL of THF and 7 mL of aqueous 1N sodium hydroxide (7 mmol). The mixturewas stirred vigorously at room temperature overnight and was then pouredinto 5 mL of water. The material was extracted three times with ethylacetate and combined organics were washed with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure to yield intermediate95 (742 mg, 84%) as a white solid.

¹H-NMR (DMSO, 400 MHz): δ 13.2 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.64 (m,1H), 7.44 (m, 1H), 7.39 (m, 1H), 7.27 (m, 1H), 5.42 (d, J=8.8 Hz, 1H),2.84 (s, 3H).

Example 94 Preparation of Intermediate 96

Following the procedure of intermediate 95, beginning with2-amino-2-(2-chlorophenyl)acetic acid (535 mg, 2.88 mmol), intermediate96 (397 mg, 52%) was synthesized as a white solid.

¹H-NMR (DMSO, 400 MHz): δ 13.2 (s, 1H), 8.21 (d, J=8.8 Hz, 1H),7.51-7.25 (m, 4H), 5.42 (d, J=8.8 Hz, 1H), 2.84 (s, 3H).

Example 95 Preparation of Intermediate 97

A solution of (R)-2-amino-2-phenylpropanoic acid (304 mg, 1.84 mmol) and0.7 mL of concentrated H₂SO₄ in 6.5 mL of anhydrous methanol was heatedovernight. After cooling to room temperature, the methanol wasconcentrated under reduced pressure. The residue was taken up in 40 mLof water and added to a separatory funnel. Solid sodium carbonate wasadded slowly until gas evolution ceased (pH 9-10). The aqueous layer wasextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with 100 mL sat. NaHCO_((aq)) and 100 mL of Brine, separated,dried (MgSO₄), filtered, and concentrated under reduced pressure toyield intermediate 97 (225 mg, 68%) as an oily residue that was used inthe next step without further purification.

¹H-NMR (DMSO, 400 MHz): δ 7.44 (m, 2H), 7.30 (m, 2H), 7.22 (m, 1H), 3.58(s, 3H), 2.36 (s, 2H), 1.50 (s, 3H)

Example 96 Preparation of Intermediate 98

To a solution of intermediate 97 (225 mg, 1.25 mmol) and pyridine (0.30mL, 3.75 mmol) in 4 mL of anhydrous CH₂CL₂, was added slowly methanesulfonylchloride (0.15 mL, 1.91 mmol). After stirring overnight, thereaction mixture was quenched with 30 mL of 1N HCl_((aq)). The aqueousmixture was extracted with ethyl acetate (3×30 mL) and combined organiclayers were washed with 1N HCl_((aq)) and then brine. The organics weredried (MgSO₄), filtered, and concentrated under reduced pressure toyield intermediate 98 (312 mg, 97%) as a yellow-green oily residue thatwas used in the next step without further purification.

LCMS m/z [M+H]⁺ C₁₁H₁₅NO₄S requires: 258.08. Found 258.31

Example 97 Preparation of Intermediate 99

Lithium hydroxide monohydrate (507 mg, 12.1 mmol) was added to asolution of intermediate 98 (310 mg, 1.2 mmol) in 15 mL of 1:1:1THF:MeOH:H₂O at room temperature. The reaction mixture was stirredovernight and then was acidified with 40 mL of 1N HCl_((aq)) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed 100 mL of brine, separated, dried (MgSO₄), filtered, andconcentrated under reduced pressure to yield intermediate 99 as an oilyresidue (285 mg, 98%).

¹H-NMR (DMSO, 400 MHz): δ 13.1 (s, 1H), 7.50 (m, 2H), 7.39 (m, 2H), 7.31(m, 1H), 2.80 (s, 3H), 1.86 (s, 3H).

Example 98 Preparation of Intermediate 100

To an oven dried 50 mL round-bottom flask, methyl2-bromo-5-methylbenzoate (352 mg, 1.54 mmol), sultam (236 mg, 1.95mmol), cesium carbonate (732 mg, 2.25 mmol), palladium acetate (40.4 mg,0.18 mmol), and Xanphos (136 mg, 0.235 mmol) were added and flask wasplaced under argon. The reagents were suspended in 8 mL of anhydrousdioxane and mixture was heated at 100° C. overnight. After cooling toroom temperature, the reaction mixture was filtered, washing with ethylacetate. The combined filtrate was concentrated under reduced pressureand resulting film was purified by silica gel column chromatography(25-100% ethyl Acetate in hexanes) to yield intermediate 100 (322 mg,78%) as a yellow off-white solid.

¹H-NMR (DMSO, 400 MHz): δ 7.75 (d, 1H), 7.44 (m, 1H), 7.35 (m, 1H), 3.89(s, 3H), 3.81 (t, 2H), 3.28 (t, 2H), 2.55 (m, 2H), 2.39 (s, 3H).

LCMS m/z [M+H]⁺ C₁₂H₁₅NO₄S requires: 270.07. Found 270.12.

Example 99 Preparation of Intermediate 101

Lithium hydroxide monohydrate (496 mg, 11.8 mmol) was added to asolution of intermediate 100 (316 mg, 1.17 mmol) in 22 mL of THF and 12mL of water at room temperature. The reaction mixture was heated at 60°C. for two hours. After cooling to room temperature, the reactionmixture was acidified with 40 mL of 1N HCl_((aq)) and extracted withethyl acetate (3×30 mL). The combined organic layers were washed 50 mLof brine, separated, dried (MgSO₄), filtered, and concentrated underreduced pressure to yield intermediate 101 as an off-white solid (293mg, 98%).

¹H-NMR (DMSO, 400 MHz): δ 12.9 (s, 1H), 7.57 (d, J=1.6 Hz, 1H),7.41-7.34 (m, 2H), 3.66 (t, J=6.8 Hz, 2H), 3.28 (m, 2H), 2.37 (m, 2H),2.33 (s, 3H).

LCMS m/z [M+H]⁺ C₁₁H₁₃NO₄S requires: 254.06. Found 254.18.

Example 100 Preparation of Intermediate 102

DMF (0.070 mL, 0.908 mmol) was added slowly to a suspension of5-methyl-2-(methylsulfonamido)benzoic acid (1.01 g, 4.59 mmol) andoxalyl chloride (1.6 mL, 18.3 mmol) in 11 mL of anhydrousdichloromethane. After 3 hours, the reaction mixture was concentratedand dried in-vacuo to yield intermediate 102 as a yellow solid (987 mg,90%) which was used in the next step without further purification.

¹H-NMR (CDCl₃, 400 MHz): δ 10.2 (s, 1H), 7.92 (s, 1H), 7.64 (m, 1H),7.39 (m, 1H), 3.03 (s, 3H), 2.35 (s, 3H).

Example 101 Preparation of Intermediate 103

A solution of 2-amino-5-chloro-3-methylbenzoic acid (928 mg, 4.99 mmol)and 2.0 mL of concentrated H₂SO₄ in 15 mL of anhydrous methanol washeated for 66 hours. After cooling to room temperature, the methanol wasconcentrated under reduced pressure. The residue was taken up in 50 mLof water and added to a separatory funnel. Solid sodium carbonate wasadded slowly until gas evolution ceased (pH 9-10). The aqueous layer wasextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with 100 mL sat. NaHCO_(3(aq)) and 100 mL of brine, separated,dried (MgSO₄), filtered, and concentrated under reduced pressure toyield intermediate 103 (817 mg, 83%) as a brown solid, which was usedwithout further purification.

¹H-NMR (CDCl₃, 300 MHz): δ 7.75 (d, J=2.7 Hz, 1H), 7.17 (d, J=2.7 Hz,1H), 5.83 (br s, 2H), 3.88 (s, 3H), 2.16 (s, 3H)

LCMS m/z [M+H]⁺ C₉H₁₀ClNO₂ requires: 200.04. Found 200.10

Example 102 Preparation of Intermediate 104

To a solution of intermediate 103 (392 mg, 1.97 mmol) and pyridine (0.45mL, 5.68 mmol) in 9 mL of anhydrous CH₂CL₂, was added slowly methanesulfonylchloride (0.46 mL, 5.66 mmol). After stirring overnight, anadditional 0.7 mL of pyridine and methane sulfonylchloride were eachadded and the reaction mixture stirred for two hour. The reactionmixture was then quenched with 30 mL of 1N HCl_((aq)). The aqueousmixture was extracted with ethyl acetate (3×40 mL) and the combinedorganic layers were washed with 1N HCl_((aq)) and then brine. Theorganics were dried (MgSO₄), filtered, and concentrated under reducedpressure to yield a light yellow film. Purification of the residue bysilica gel column chromatography (0-50% ethyl Acetate in hexanes)yielded intermediate 104 (330, 60%) as a light yellow solid.

¹H-NMR (CDCl₃, 300 MHz): δ 8.47 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.50(d, J=2.4 Hz, 1H), 3.96 (s, 3H), 2.90 (s, 3H), 2.53 (s, 3H)

LCMS m/z [M+H]⁺ C₁₀H₁₂ClNO₄S requires: 278.03. Found 278.08

Example 103 Preparation of Intermediate 105

Lithium hydroxide monohydrate (228 mg, 5.43 mmol) was added to asolution of intermediate 104 (120 mg, 0.433 mmol) in 3 mL of 1:1:1THF:MeOH:H₂O at room temperature. The reaction mixture was heated at 50°C. for four hours. After cooling to room temperature, the reactionmixture was acidified with 20 mL of 1N HCl_((aq)) and extracted withethyl acetate (3×20 mL). The combined organic layers were washed 50 mLof brine, separated, dried (MgSO₄), filtered, and concentrated underreduced pressure to yield intermediate 105 as a white solid (114 mg,100%).

¹H-NMR (DMSO, 300 MHz): δ 9.2 (s, 1H), 7.59 (m, 2H), 2.96 (s, 3H), 2.37(s, 3H) LCMS m/z [M+H]⁻ C₉H₁₀ClNO₄S requires: 264.00. Found 264.09

Example 104 Preparation of Intermediate 106

A solution of 2-amino-3-fluorobenzoic acid (559 mg, 3.62 mmol) and 1.7mL of concentrated H₂SO₄ in 11 mL of anhydrous methanol was heated for66 hours. After cooling to room temperature, methanol was concentratedunder reduced pressure. The residue was taken up in 30 mL of water andadded to a separatory funnel. Solid sodium carbonate was added slowlyuntil gas evolution ceased (pH 9-10). The aqueous layer was extractedwith ethyl acetate (3×40 mL). The combined organic layers were washedwith 100 mL sat. NaHCO_(3(aq)) and 100 mL of brine, separated, dried(MgSO₄), filtered, and concentrated under reduced pressure.

Column chromatography (5% ethyl acetate in hexanes) yielded intermediate106 (491 mg, 80%) as a white solid.

¹H-NMR (CDCl₃, 300 MHz): δ 7.66-7.63 (m, 1H), 7.15-7.08 (m, 1H),6.60-6.55 (m, 1H), 5.40 (br s, 2H), 3.89 (s, 3H),

LCMS m/z [M+H]⁺ C₈H₈FNO₂ requires: 170.05. Found 170.10

Example 105 Preparation of Intermediate 107

To a mixture intermediate 106 (334 mg, 1.97 mmol) and pyridine (0.41 mL,4.95 mmol) in 5.5 mL of dichloromethane at 0° C., was added slowlymethanesulfonyl chloride (0.40 mL, 4.95 mmol). The mixture was warmed toroom temperature and stirred overnight. HPLC indicated ˜48% conversionto desired product. Pyridine (0.55 mL) and 0.50 mL of methanesulfonylchloride (approximately 6.8 mmol each) was then added at roomtemperature. After a total of 40 hours, reaction mixture was quenchedwith 10 mL of 1N HCl. After 5 minutes of stirring, mixture was pouredinto 20 mL of water. The aqueous layer was extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with 100 mL of 1NHCl_((aq)) and 100 mL brine, separated, dried (MgSO₄), filtered, andconcentrated under reduced pressure. Column chromatography (15-50% ethylacetate in hexanes) yielded intermediate 107 (360 mg, 74%) as a whitesolid.

¹H-NMR (CDCl₃, 300 MHz): δ 9.79 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.35(m, 1H), 7.19-7.17 (m, 1H), 3.96 (s, 3H), 7.21-3.35 (s, 3H)

LCMS m/z [M+H]⁺ C₉H₁₀FNO₄S requires: 248.03. Found 248.08

Example 106 Preparation of Intermediate 108

A solution of NaOH in water (2.85 M, 3 mL, 8.55 mmol) was added to asolution of intermediate 107 in 8.5 mL of THF with strong stirring. Thereaction mixture was stirred at room temperature overnight. The mixturewas then acidified with 15 mL of 1N HCl and extracted with ethyl acetate(3×30 mL). The combined organic layers were washed 80 mL of brine,separated, dried (MgSO₄), filtered, and concentrated under reducedpressure to yield intermediate 108 as a white solid (284 mg, 91%).

¹H-NMR (DMSO, 300 MHz): δ 9.77 (s, 1H), 7.70-7.68 (m, 1H), 7.57-7.50 (m,1H), 7.38-7.33 (m, 1H), 3.15 (s, 3H)

LCMS m/z [M+H]⁺ C₉H₁₀FNO₄S requires: 234.02. Found 234.09

Example 107 Preparation of Intermediate 109

N-chlorosuccinimide (528 mg, 3.95 mmol) was added to a solution of5-fluoro-2-(methylsulfonamido)benzoic acid (705 mg, 3.03 mmol) in 9 mLof anhydrous DMF. After stirring overnight, the reaction mixture waspoured into 100 mL of water and 50 mL of brine and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with 300 mLof 1:1 water:brine, dried (MgSO₄), filtered, and concentrated underreduced pressure to yield intermediate 109 (746 mg, 93%).

¹H-NMR (DMSO, 400 MHz): δ 9.5 (s, 1H), 7.76 (dd, J_(HF)=8 Hz, J_(HH)=3Hz, 1H), 7.52 (dd, J_(HF)=8 Hz, J_(HH)=3 Hz, 1H), 3.01 (s, 3H)

LCMS m/z [M+H]⁻ C₈H₇ClFNO₄S requires: 265.98. Found 265.09

Example 108 Preparation of Intermediate 112

A solution of (S)-2-amino-2-phenylpropanoic acid (246.2 mg, 1.49 mmol)and 0.6 mL of concentrated H₂SO₄ in 6 mL of anhydrous methanol washeated overnight. After cooling to room temperature, the methanol wasconcentrated under reduced pressure. The residue was taken up in 20 mLof water and added to a separatory funnel. Solid sodium carbonate wasadded slowly until gas evolution ceased (pH 9-10). The aqueous layer wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with 80 mL sat. NaHCO_(3(aq)) and 80 mL of Brine, separated,dried (MgSO₄), filtered, and concentrated under reduced pressure toyield intermediate 112 (117 mg, 44%) as a yellow-green oily residue.

¹H-NMR (DMSO, 400 MHz): δ 7.44 (m, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 3.59(s, 3H), 2.37 (s, 2H), 1.51 (s, 3H)

LCMS m/z [M+H]⁺ C₁₀H₁₃NO₂ requires: 180.09. Found 180.19

Example 109 Preparation of Intermediate 113

To a solution of intermediate 112 (116 mg, 0.647 mmol) and pyridine(0.16 mL, 1.98 mmol) in 4 mL of anhydrous CH₂CL₂, was added slowlymethane sulfonylchloride (0.070 mL, 0.91 mmol). After stirringovernight, the reaction mixture was quenched with 20 mL of 1NHCl_((aq)). The aqueous mixture was extracted with ethyl acetate (3×20mL) and combined organic layers were washed with 1N HCl_((aq)) and thenbrine. The organics were dried (MgSO₄), filtered, and concentrated underreduced pressure to yield intermediate 113 (312 mg, 97%) as ayellow-green oily residue that was used in the next step without furtherpurification.

LCMS m/z [M+H]⁺ C₁₁H₁₅NO₄S requires: 258.08. Found 258.19

Example 110 Preparation of Intermediate 114

Lithium hydroxide monohydrate (169 mg, 4.02 mmol) was added to asolution of intermediate 113 (102 mg, 0.397 mmol) in 6 mL of 1:1:1THF:MeOH:H₂O at room temperature. The reaction mixture was stirredovernight and then was acidified with 15 mL of 1N HCl_((aq)), andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed 50 mL of brine, separated, dried (MgSO₄), filtered, andconcentrated under reduced pressure to yield intermediate 114 as a lightgreen film (93.6 mg, 97%).

LCMS m/z [M+H]⁺ C₁₀H₁₃NO₄S requires: 242.06. Found 242.10.

Example 111 Preparation of Intermediate 115

Step 1: Sodium azide (158 mg, 2.43 mmol) was added to a solution ofmethyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL ofDMF at room temperature. After stirring overnight, reaction mixture wasquenched with 25 mL of water. The aqueous was extracted with ethylacetate (3×30 mL) and the combined organics were washed with water (2×40mL) and 50 mL of brine. The organics were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to yield methyl2-(azidomethyl)-5-chlorobenzoate (429 mg, 97%) as an off-white solid,which was used in the next step without further purification.

Step 2: Lithium hydroxide monohydrate (794 mg, 18.9 mmol) was added to asolution of methyl 2-(azidomethyl)-5-chlorobenzoate (426 mg, 1.88 mmol),from the previous step, in 27 mL of 1:1:1 THF:methanol:water at roomtemperature. After stirring overnight, the reaction mixture was quenchedwith 20 mL, of 2N HCl_((aq)), and extracted with ethyl acetate (3×30mL). The combined organics were washed with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure to yield intermediate115 (395 mg, 99%) as a white solid.

¹H-NMR (DMSO, 400 MHz): δ 7.88 (m, 1H), 7.70-7.65 (m, 1H), 7.54 (m, 1H),4.78 (s, 2H).

Example 112 Preparation of Intermediate 116

Following the procedure of intermediate 95, beginning with2-amino-2-(2-fluorophenyl)acetic acid (1.27 g, 7.51 mmol), intermediate116 (1.33 g, 72%) was synthesized as a yellow solid.

Example 113 Preparation of Intermediate 117

Following the procedure for synthesis of intermediate 88, but beginningwith intermediate 87 (53 mg, 0.133 mmol) and5-methyl-2-(methylsulfonamido)benzoic acid (42 mg, 0.183 mmol),intermediate 117 (31 mg, 38%) was recovered as a clear film.

LCMS m/z [M+H]⁺ C₃₀H₄₁N₇O₅S requires: 612.29. Found 612.31.

Example 114 Preparation of Intermediate 118

To mixture of tert-butyl 3,6-diazabicyclo[3.1.0]hexane-3-carboxylate (50mg, 0.271 mmol) and triethylamine (38 μL, 0.271 mmol) in dichloromethane(1.4 ml) was added 4-nitrobenzene-1-sulfonyl chloride (60 mg, 0.271mol). After 6.5 h, the reaction mixture was purified directly by silicagel chromatography using a gradient of hexanes/ethyl acetate 1:0 to 0:1to afford intermediate 118 (57 mg, 52%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J=8.9 Hz, 2H), 8.16 (d, J=8.9 Hz,2H), 3.76-3.67 (m, 3H), 3.62 (dd, J=5.6, 2.6 Hz, 1H), 3.45-3.37 (m, 1H),1.41 (s, 9H).

Example 115 Preparation of Intermediate 119

To mixture of intermediate 118 (57 mg, 0.141 mmol) in acetonitrile (564μL) and water (141 μL) was added sodium cyanide (10.4 mg, 0.21 mmol).After 24 h, the reaction mixture was purified directly by silicapreparatory HPLC (Gemini C18, 100×30 mm, 5 micron column) using agradient of water/acetonitrile (with 0.1% TFA modifier) 75:15 to 0:1. Tothe resulting intermediate in dichloromethane (1 mL) was addedtrifluoroacetic acid (1 mL). After 2 h, the reaction mixture wasconcentrated to afford intermediate 119 (20 mg, 37%) as a colorless oil.

LCMS (m/z) 297.04 [M+H], t_(r)=1.63 min.

Example 116 Preparation of Intermediate 120

To a suspension of (5-chloro-2-(methylsulfonamido)benzoic acid) (0.7 g,2.8 mmol) in DCM (6 ml) was added oxalylchloride (2 M in DCM, 6 ml, 12mmol) and DMF (5 microliter) and the material was stirred for 3 h atroom temperature. The volatiles were removed under vacuum to affordintermediate 120 as a crude residue that was used without furtherpurification.

Example 117 Preparation of Compound 1

To a solution of intermediate 32 (20.0 mg, 0.036 mmol) in MeOH (1.00 mL)was added 3-methylazetidine hydrochloride (165 mg, 0.72 mmol) andtriethylamine (200 μL, 1.44 mmol), and the reaction mixture was stirredat 70° C. After 2 h, the reaction mixture was allowed to cool to roomtemperature and was concentrated under reduced pressure. The cruderesidue was purified by preparatory HPLC (5-100% MeCN/H₂O, 0.1%trifluoroacetic acid modifier) to afford compound 1 (28 mg, 96%) as awhite solid.

LCMS (m/z) 588.20 [M+H]⁺

MW 587.21

Example 118 Preparation of Compound 2

To a solution of intermediate 11 (30.0 mg, 0.06 mmol) in MeOH (1.0 mL)was added (S)-2-aminopropan-1-ol (47 mg, 0.62 mmol) and triethylamine(174 μL, 1.25 mmol), and the reaction mixture was stirred at 70° C.After 2 h, the reaction mixture was allowed to cool to room temperatureand was concentrated under reduced pressure. The crude residue waspurified by preparatory HPLC (5-100%/MeCN/H₂O, 0.1% trifluoroacetic acidmodifier) to afford compound 2 (6.7 mg, 22%) as a white solid. (TFASalt).

LCMS (m/z) 521.10 [M+H]⁺

MW 520.17

Example 119 Preparation of Compound 3

To a solution of intermediate 11 (25 mg, 0.05 mmol) in MeOH (0.5 mL) wasadded intermediate 119 (20 mg, 0.047 mmol) and triethylamine (174 μL,1.25 mmol), and the reaction mixture was stirred at 70° C. After 2 h,the reaction mixture was allowed to cool to room temperature and wasconcentrated under reduced pressure. To the resulting residue was addedDMF (0.5 mL) and DBU (40.0 μL, 0.268 mmol) followed by 2-mercaptoaceticacid (5 L, 0.07 mmol). After 18 h, the reaction mixture was purified bypreparatory HPLC (5-100% McCN/H₂O, 0.1% trifluoroacetic acid modifier)to afford compound 3 (4.2 mg, 14%, 1:1 diastereomeric mixture) as awhite solid. (TFA Salt)

LCMS (m/z) 557.10 [M+H]⁺

MW 556.18

Example 120 General Procedure for the Preparation of Compounds 4-18

In 50 mL, singled necked, round bottomed flask was placed intermediate12 (2640 mg, 6.59 mmol) and TEA (1.83 mL, 13.2 mmol) in DMF (8.8 mL).The carboxylic acids (B2) (between 0.10 mmol and 0.50 mmol) were placedin separate 2-ml vials. Then, into each vial was dispensed a solution ofintermediate 12 (0.050 mmol) followed by the addition of HATU (38 mg,0.10 mmol). The resulting reaction mixtures were stirred at roomtemperature for 16 h. Then, to each reaction mixture was added EtOAc (4mL), washed with sat. NaHCO₃ (2 mL×2), and concentrated to give thecoupled products (B3) as a crude solid. The crude product wasredissolved in dichloromethane (0.5 mL) followed by the addition of TFA(0.2 mL). After the reaction mixture was stirred at room temperature for1 h, it was loaded onto the CUBCX column. The mixture was washed withMeOH:EtOAc (1:4, 4 mL) and MeOH:dichloromethane (1:4, 4 mL), eluted with7 N NH₄OMe:EtOAc (3:7, 4 mL), and concentrated to afford the finalcompound (i.e. compounds 4-18).

Example 121 Preparation of Compound 4

The title compound was prepared in 15% yield according to the generalprocedure of Example 120 starting from intermediate 12 and2,4-dimethylbenzoic acid.

LCMS (m/z) 433.46 [M+H]⁺

MW 432.26

Example 122 Preparation of Compound 5

The title compound was prepared in 65% yield according to the generalprocedure of Example 120 starting from intermediate 12 and benzoic acid.

LCMS (m/z) 405.48 [M+H]⁺

MW 404.23

Example 123 Preparation of Compound 6

The title compound was prepared in 95% yield according to the generalprocedure of Example 120 starting from intermediate 12 and3-methylpicolinic acid.

LCMS (m/z) 420.33 [M+H]⁺

MW 419.24

Example 124 Preparation of Compound 7

The title compound was prepared in 80% yield according to the generalprocedure of Example 120 starting from intermediate 12 and4-methylnicotinic acid.

LCMS (m/z) 420.41 [M+H]⁺

MW 419.24

Example 125 Preparation of Compound 8

The title compound was prepared in 89% yield according to the generalprocedure of Example 120 starting from intermediate 12 and2-methoxy-5-methylbenzoic acid.

LCMS (m/z) 449.36 [M+H]⁺

MW 448.26

Example 126 Preparation of Compound 9

The title compound was prepared in 68% yield according to the generalprocedure starting from intermediate 12 and 2-(trifluoromethoxy)benzoicacid.

LCMS (m/z) 489.30 [M+H]⁺

MW 448.21

Example 127 Preparation of Compound 10

The title compound was prepared in 39% yield according to the generalprocedure of Example 120 starting from intermediate 12 and5-chloro-2-methoxybenzoic acid.

LCMS (ml/z) 469.30 [M+H]⁺

MW 468.20

Example 128 Preparation of Compound 11

The title compound was prepared in 67% yield according to the generalprocedure of Example 120 starting from intermediate 12 and intermediate101

LCMS (m/z) 538.14 [M+H]⁺

MW 537.25

Example 129 Preparation of Compound 12

The title compound was prepared in 23% yield according to the generalprocedure of Example 120 starting from intermediate 12 and5-methyl-3-(methylsulfonamido)thiophene-2-carboxylic acid.

LCMS (m/z) 518.04 [M+H]⁺

MW 517.19

Example 130 Preparation of Compound 13

The title compound was prepared according to the general procedure ofExample 120 starting from intermediate 12 and2-acetamidothiophene-3-carboxylic acid.

LCMS (m/z) 468.4 [M+H]⁺

MW 467.21

Example 131 Preparation of Compound 14

The title compound was prepared according to the general procedure ofExample 120 starting from intermediate 12 and 2-amino-5-methylnicotinicacid.

LCMS (m/z) 435.4 [M+H]⁺

MW 434.25

Example 132 Preparation of Compound 15

The title compound was prepared according to the general procedure ofExample 120 starting from intermediate 12 and5-fluoro-1H-indazole-3-carboxylic acid.

LCMS (m/z) 463.4 [M+H]⁺

MW 462.23

Example 133 Preparation of Compound 16

The title compound was prepared according to the general procedure ofExample 120 starting from intermediate 12 and 2-hydroxy-3-methylbenzoicacid.

LCMS (m/z) 435.4 [M+H]⁺

MW 434.24

Example 134 Preparation of Compound 17

The title compound was prepared according to the general procedure ofExample 120 starting from intermediate 12 and 1H-indole-2-carboxylicacid.

LCMS (m/z) 444.4 [M+H]⁺

MW 443.24

Example 135 Preparation of Compound 18

The title compound was prepared in 92% yield according to the generalprocedure of Example 120 starting from intermediate 12 and3-chloropicolinic acid.

LCMS (m/z) 440.05 [M+H]⁺

MW 439.19

Example 136 Preparation of Compound 19

(R)-piperazin-2-ylmethanol (11.6 uL, 0.10 mmol) and sodium bicarbonate(16.0 mg, 0.20 mmol) were added to a solution of intermediate 33 (50 mg,0.10 mmol) in acetonitrile (0.50 mL) and water (0.50 mL) and thereaction mixture was stirred at room temperature. After 12 h, azetidinehydrochloride (46.0 mg, 0.50 mmol) was added and the reaction mixturewas stirred at 70° C. After 5 h, the reaction mixture was allowed tocool to room temperature and was concentrated under reduced pressure.The crude residue was purified by preparatory HPLC (5-100% MeCN/H₂O,0.1% trifluoroacetic acid modifier) to afford compound 19 (16 mg, 22%)as a white solid.

LCMS (m/z) 603.14 [M+H]⁺

MW 602.22

Example 137 Preparation of Compound 20

Ethane-1,2-diamine (6.7 μL, 0.10 mmol) and sodium bicarbonate (16.0 mg,0.20 mmol) were added to a solution of intermediate 33 (50 mg, 0.10mmol) in acetonitrile (0.50 mL) and water (0.50 mL) and the reactionmixture was stirred at room temperature. After 12 h, azetidinehydrochloride (46.0 mg, 0.50 mmol) was added and the reaction mixturewas stirred at 70° C. After 5 h, the reaction mixture was allowed tocool to room temperature and was concentrated under reduced pressure.The crude residue was purified by preparatory HPLC (5-100% MeCN/H₂O,0.1% trifluoroacetic acid modifier) to afford compound 20 (2 mg, 3%) asa white solid.

LCMS (m/z) 547.13 [M+H]⁺

MW 546.19

Example 138 Preparation of Compound 21

To a solution of intermediate 11 (30.0 mg, 62.0 mol) in MeOH (1 mL) wasadded (S)-tert-butyl-pyrrolidin-3-ylmethylcarbamate (146 mg, 0.62 mmol)and triethylamine (174 μL, 1.25 mmol) at room temperature, and thereaction mixture was heated to 70° C. After 12 h, the reaction mixturewas allowed to cool to room temperature and was purified by preparatoryHPLC (5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier).Trifluoroacetic acid (1 mL) was added at room temperature. After 30 min,the resulting mixture was concentrated to afford compound 21 (40.0 mg,98%) as a light yellow solid trifluoroacetate salt.

LCMS (ESI) m/z 546.19 [M+H]⁺, t_(R)=1.95 min.

MW 545.20

Example 139 Preparation of Compound 22

HATU (57 mg, 0.149 mmol) was added to a solution of intermediate 96 (34mg, 0.129 mmol) 1.2 mL of DMF at room temperature. After 60 minutes ofstirring, intermediate 7 (22 mg, 0.067 mmol) was added followedimmediately by triethylamine (0.023 mL, 0.168 mmol).

Reaction mixture stirred at room temperature overnight under argon.Mixture was then poured into 30 mL of H₂O and extracted three times with30 mL of ethyl acetate. The combined organic layers were washed with 50mL brine, dried (MgSO₄), filtered, and concentrated under reducedpressure leaving a residue that was purified by prep HPLC (15-100%Acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1%trifluoroacetic acid)) to yield compound 22 as a solid (5 mg, 11%)trifluoroacetic acid salt (˜1:1 mixture of diastereomers), afterlyophilization

LCMS m/z [M+H]⁺ C₂₆H₃₀ClN₇O₄S requires: 572.18. Found 572.08.

HPLC Tr (min), purity %: 5.65, 88%.

Example 140 Preparation of Compound 23

Following the procedure for the synthesis of compound 22, beginning withintermediate 95 (40 mg, 0.130 mmol) and intermediate 7 (25 mg, 0.076mmol), compound 23 was synthesized as a solid (7 mg, 13%)trifluoroacetic acid salt(˜1:1 mixture of diastereomers), afterlyophilization

LCMS m/z [M+H]⁺ C₂₆H₃₀BrN₇O₄S requires: 616.13. Found 615.98.

HPLC Tr (min), purity %: 5.69, 93%.

Example 141 Preparation of Compound 24

Following the synthesis of compound 22, beginning with intermediate 109(31.4 mg, 0.117 mmol), and intermediate 24 (30.6 mg, 0.09 mmol) andtriethylamine (0.045 mL, 0.315 mmol), compound 24 (38 mg, 68%) wassynthesized as a white solid, trifluoroacetic acid salt afterlyophilization.

LCMS m/z [M+H]⁺ C₂₂H₂₆ClN₆O₃S requires: 509.15. Found 509.30.

HPLC Tr (min), purity %: 5.00, 99%.

Example 142 Preparation of Compound 25

Following the synthesis of compound 22, beginning with intermediate 105(21.5 mg, 0.081 mmol), and intermediate 24 (20.1 mg, 0.06 mmol) andtriethylamine (0.030 mL, 0.210 mmol), compound 25 (29 mg, 77%) wassynthesized as a white solid, trifluoroacetic acid salt afterlyophilization.

LCMS m/z [M+H]⁺ C₂₃H₂₉ClN₆O₃S requires: 505.17. Found 505.32.

HPLC Tr (min), purity %: 5.58, 99%.

Example 143 Preparation of Compound 26

Following the synthesis of compound 22, beginning with3,5-dichloro-2-(methylsulfonamido)benzoic acid (58 mg, 0.204 mmol), a0.5 M DMF solution of intermediate 26 (0.3 mL, 0.15 mmol) andtriethylamine (0.060 mL, 0.420 mmol), compound 26 (69 mg, 72%) wassynthesized as a white solid, trifluoroacetic acid salt afterlyophilization.

LCMS m/z [M+H]⁺ C₂₃H₂₅Cl₂NO₃S requires: 522.11. Found 522.41.

HPLC Tr (min), purity %: 7.19, 99%.

Example 144 Preparation of Compound 27

HATU (150 mg, 0.394 mmol) was added to a solution of intermediate 99 (80mg, 0.33 mmol) in 3.3 mL of DMF at room temperature. After 45 min ofstirring, intermediate 12 (106 mg, 0.266 mmol) was added followedimmediately by triethylamine (0.090 mL, 0.639 mmol). Reaction mixturestirred at room temperature overnight under argon. Mixture was thenpoured into 30 mL of H₂O and extracted three times with 30 mL of ethylacetate. The combined organic layers were washed with 50 mL brine, dried(MgSO₄), filtered, and concentrated under reduced pressure leaving aresidue, which was dissolved in 7 mL of dichloromethane. Trifluoroaceticacid (0.7 mL, 8.9 mmol) was added and reaction mixture stirred at roomtemperature for 18 hours. Mixture was then concentrated under reducedpressure and purified by prep HPLC (15-100% Acetonitrile (with 0.1%trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) toyield compound 27 (7.5 mg, 5%) as a white solid, trifluoroacetic acidsalt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₆H₃₅N₇O₃S requires: 526.25. Found 526.18.

HPLC Tr (min), purity %: 4.87, 96%.

Example 145 Preparation of Compound 28

Intermediate 114 (59 mg, 0.243 mmol) was suspended in neat thionylchloride (2 mL, 27.5 mmol) at room temperature. Mixture was heated at70° C. overnight. After cooling to room temperature, reaction mixturewas concentrated, yielding a residue. To a solution of this residue in 2mL of dichloromethane, was added intermediate 12 (78 mg, 0.195 mmol) andtriethylamine (0.040 mL, 0.283 mmol) and mixture was stirred at roomtemperature overnight. Reaction mixture was concentrated under reducedpressure and residue was purified by silica gel column chromatography(10-80% ethyl acetate in hexanes) to yield 27 mg of desired precursor,which was dissolved in 2 mL of dichloromethane and treated withtrifluoroacetic acid (0.150 mL, 1.95 mmol). After stirring for one hourat room temperature, reaction mixture was concentrated under reducedpressure to yield compound 28 (26 mg, 17% over 3 steps), as anorange-yellow solid, trifluoroacetic acid salt.

LCMS m/z [M+H]⁺ C₂₆H₃₅N₇O₃S requires: 526.25. Found 526.19.

HPLC Tr (min), purity %: 4.88, 97%.

Example 146 Preparation of Compound 29

N-chlorosuccinimde (99.4 mg, 0.744 mmol) was added to a solution ofintermediate 108 (142 mg, 0.609 mmol) in 3.5 mL of DMF at roomtemperature. After stirring overnight, reaction mixture was poured intowater and extracted three times with ethyl acetate. Combined organicswere washed with water and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to yield5-chloro-3-fluoro-2-(methylsulfonamido)benzoic acid (142 mg, 87%, 90%HPLC purity) which was used without further purification. HATU (87.4 mg,0.230 mmol) was added to a solution of5-chloro-3-fluoro-2-(methylsulfonamido)benzoic acid (55.1 mg, 0.206mmol) in 5 mL of DMF at room temperature. After 45 minutes, a 0.5 M DMFsolution of intermediate 26 (0.3 mL, 0.15 mmol) and triethylamine (0.050mL, 0.375 mmol) were added. Reaction mixture stirred at room temperatureovernight under argon. Mixture was then poured into 50 mL of H₂O andextracted three times with 30 mL of ethyl acetate. The combined organiclayers were washed with 50 mL brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure leaving a residue. Product waspurified by prep HPLC (15-100% Acetonitrile (with 0.1% trifluoroaceticacid) in water (with 0.1% trifluoroacetic acid)) to yield compound 29(28 mg, 31%) as a white solid trifluoroacetic acid salt, afterlyophilization.

LCMS m/z [M+H]⁺ C₂₃H₂₅ClFN₅O₃S requires: 506.14. Found 506.07.

HPLC Tr (min), purity %: 7.52, 99%.

Example 147 Preparation of Compound 30 and Compound 31

Following the procedure of compound 29, beginning with an ˜5:1 mixtureof 5-chloro-4-fluoro-2-(methylsulfonamido)benzoic acid and intermediate43 (53 mg, 0.198 mmol), a 0.5 M DMF solution of intermediate 26 (0.3 mL,0.15 mmol) and triethylamine (0.060 mL, 0.420 mmol), compound 30 (36 mg,39%) and compound 31 (7 mg, 8%) were synthesized as white solids,trifluoroacetic acid salts after lyophilization.

Compound 30: LCMS m/z [M+H]⁺ C₂₃H₂₅ClFN₅O₃S requires: 506.14. Found506.12.

HPLC Tr (min), purity %: 7.62, 98%.

Compound 31: LCMS m/z [M+H]⁺ C₂₃H₂₅ClFN₅O₃S requires: 506.14. Found506.10.

HPLC Tr (min), purity %: 6.73, 99%.

Example 148 Preparation of Compound 32

Following the synthesis of compound 22, beginning with intermediate 109(15.1 mg, 0.056 mmol), and intermediate 22 and triethylamine (0.020 mL,0.137 mmol), compound 32 (13 mg, 55%) was synthesized as a white solid,trifluoroacetic acid salt after lyophilization.

LCMS m/z [M+H]⁺ C₂₂H₂₅ClFN₅O₃S requires: 494.14. Found 494.30.

IPLC Tr (min), purity %: 6.19, 95%.

Example 149 Preparation of Compound 33

Following the synthesis of compound 27, beginning with intermediate 95(148 mg, 0.795 mmol) and intermediate 12 (82 mg, 0.151 mmol), compound33 (89 mg, 84% over two steps) was synthesized as a white solid,trifluoroacetic acid salt (˜1:1 mixture of diastereomers).

LCMS m/z [M+H]⁺ C₂₅H₃₂BrN₇O₃S requires: 590.15. Found 590.33.

HPLC Tr (min), purity %: 4.93, 99%.

Example 150 Preparation of Compound 34

Following the synthesis of compound 27, beginning with intermediate 96(48 mg, 0.183 mmol) and intermediate 12 (49 mg, 0.122 mmol), compound 34(47 mg, 58% over two steps) was synthesized as a white solid,trifluoroacetic acid salt (˜1:1 mixture of diastereomers).

LCMS m/z [M+H]C₂₅H₃₂ClN₇O₃S requires: 546.20. Found 546.32.

HPLC Tr (min), purity %: 4.88, 96%.

Example 151 Preparation of Compound 35

Following the BOC deprotection step in the synthesis of compound 27, butbeginning with intermediate 38 (11 mg), compound 35 (11 mg, 99%) wassynthesized as a white solid film.

LCMS m/z [M+H]⁺ C₂₄H₂₁ClN₉O requires: 494.21. Found 494.09.

HPLC Tr (min), purity %: 5.24, 99%.

Example 152 Preparation of Compound 36

Step 1: Triphenylphosphine (87 mg, 0.332 mmol) was added to a solutionof intermediate 38 (97 mg, 0.163 mmol) in 5 mL of THF at roomtemperature. After 90 minutes, 0.2 mL of water was added and mixture washeated at 60° C. overnight. Reaction mixture was concentrated underreduced pressure and purified by silica gel column chromatography (0-10%methanol in dichloromethane) to yield the intermediate benzylamine (44mg, 48%).

Step 2: Previous intermediate from step 1 was dissolved in 2 mL ofdichloromethane and triethylamine (0.035 mL, 0.249 mmol) was added.Solution was cooled to 0° C. and methane sulfonylchloride (0.020 mL,0.238 mmol) was added. Reaction mixture was warmed to room temperature,stirred overnight, then concentrated under reduced pressure. Residue waspurified by silica gel column chromatography (10-90% ethyl acetate inhexanes) to yield the intermediate benzylsulfonamide (35 mg, 78%).

Step 3: Previous intermediate from step 2 (27 mg, 0.042 mmol) wasdissolved in 1.5 mL of dichloromethane at room temperature.Trifluoroacetic acid (0.135 mL, 1.74 mmol) was added and reactionmixture stirred overnight. Reaction mixture was concentrated underreduced pressure to yield compound 36 (26 mg, 99%) as a white solidfilm, trifluoroacetic acid salt.

LCMS m/z [M+H]⁺ C₂₅H₃₂ClN₇O₃S requires: 546.20. Found 546.32.

HPLC Tr (min), purity %: 4.96, 99%.

Example 153 Preparation of Compound 37

Intermediate 39 (5 mg, 0.00882 mmol) was dissolved in 0.5 mL ofdichloromethane at room temperature. Trifluoroacetic acid (0.03 mL,0.386 mmol) was added and mixture stirred at room temperature for onehour. Reaction mixture was then concentrated under reduced pressure toyield compound 37 (6.6 mg, 93%) as the bis-trifluoroacetic acid salt.

LCMS m/z [M+H]⁺ C₂₄H₃ClN₇O requires: 468.22. Found 468.09.

HPLC Tr (min), purity %: 4.32, 97%.

Example 154 Preparation of Compound 38 and Compound 39

A dioxane solution of hydrochloric acid (4N, 1.25 mL, 5 mmol) was addedto a solution of intermediate 54 (106 mg, 0.5 mmol) in 6 mL of dioxane.After stirring for eighteen hours, solvent was concentrated underreduced pressure resulting in a residue that was dissolved in 4 mL ofmethanol and treated with intermediate 11 (41.4 mg, 0.0858 mmol) andtriethylamine (0.14 mL, 1.00 mmol). Mixture was heated at 75° C.overnight. After cooing to room temperature, reaction mixture wasconcentrated under reduced pressure, resulting in a residue.Purification via prep HPLC (15-100% Acetonitrile (with 0.1%trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) yieldedcompound 38 (18 mg, 19%) and compound 39 (3 mg, 3%) as white solids,trifluoroacetic acid salts, after lyophilization.

Compound 38: LCMS m/z [M+H]⁺ C₂₅H₃₀ClN₇O₅S requires: 576.17. Found576.44.

HPLC Tr (min), purity %: 5.36, 99%

Compound 39: LCMS m/z [M+H]⁺ C₂₅H₃₀ClN₇O₅S requires: 576.17. Found576.43.

HPLC Tr (min), purity %: 5.51, 76%

Example 155 Preparation of Compound 40

Following the procedure of the second step of Example 154, beginningwith intermediate 11 (50 mg, 0.104 mmol) and 2-methylazetidinehydrochloride (72 mg, 0.669 mmol), compound 40 (43 mg, 80%) wassynthesized as a white solid (˜1:1 mixture of diastereomers).

LCMS m/z [M+H]⁺ C₂₄H₂₉CLN₆O₃S requires: 517.17. Found 517.06.

HPLC Tr (min), purity %: 6.62, 96%.

Example 156 Preparation of Compound 41

Following the procedure of the second step of Example 154, beginningwith intermediate 11 (54 mg, 0.112 mmol) and 3-ethynylpyrrolidine2,2,2-trifluoroacetate (108 mg, 0.519 mmol), compound 41 (59 mg, 96%)was synthesized as a white solid (˜1:1 mixture of diastereomers).

LCMS m/z [M+H]⁺ C₂₆H₂₉ClN₆O₃S requires: 541.17. Found 541.07.

HPLC Tr (min), purity %: 7.25, 99%.

Example 157 Preparation of Compound 42

Triethylamine (0.100 mL, 0.717 mmol) was added to a mixture ofintermediate 11 (71 mg, 0.147 mmol) and tert-butyl1,6-diazaspiro[3.3]heptane-6-carboxylate (114 mg, 0.575 mmol) in 5 mL ofmethanol at room temperature. After heating at 75° C. overnight,reaction mixture was cooled to room temperature and concentrated underreduced pressure. The remaining residue was purified by silica gelcolumn chromatography (5-75% ethyl acetate in hexanes) to yield(S)-tert-butyl1-(2-(1-(5-chloro-2-(methylsulfonamido)benzoyl)piperidin-2-yl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)-1,6-diazaspiro[3.3]heptane-6-carboxylateas a solid (33 mg, 35%). This solid was dissolved in 3 mL ofdichloromethane and trifluoroacetic acid (0.15 mL, 1.95 mmol) was added.After stirring overnight and reaction mixture was concentrated underreduced pressure to yield compound 42 (33 mg, 99%) as a white solid.

LCMS m/z [M+H]⁺ C₂₅H₃₀ClN₇O₃ requires: 544.18. Found 544.37.

HPLC Tr (min), purity %: 5.67, 96%.

Example 158 Preparation of Compound 43

Sodium bicarbonate (54 mg, 0.643 mmol) and piperazine-2-carbonitrilebishydrochloride (38 mg, 0.206 mmol) were added to a solution ofintermediate 33 (99 mg, 0.197 mmol). Mixture was stirred vigorously atroom temperature overnight. Mixture was then filtered, concentratedunder reduced pressure, and residue was purified by silica gel columnchromatography to yieldN-(4-chloro-2-((2S)-2-(5-chloro-7-(3-cyanopiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)phenyl)methanesulfonamide(30 mg, 26%). This yellow film (27 mg, 0.047 mmol) was dissolved in 3 mLof THF and azetidine hydrochloride (22 mg, 0.237 mmol) and triethylamine(0.066 mL, 0.470 mmol) were added. Reaction mixture was heated at 70° C.overnight. Reaction mixture was then cooled to room temperature,concentrated under reduced pressure, and resulting residue was purifiedby prep HPLC (15-100% Acetonitrile (with 0.1% trifluoroacetic acid) inwater (with 0.1% trifluoroacetic acid)) to yield compound 43 (10 mg,30%) as a light yellow solid trifluoroacetic acid salt, afterlyophilization (˜1:1 mixture of diastereomers).

LCMS m/z [M+H]⁺ C₂₇H₃₂ClN₉O₃S requires: 597.21. Found 597.17.

HPLC Tr (min), purity %: 4.79, 91%.

Example 159 Preparation of Compound 44

Following the procedure of compound 42, beginning with intermediate 28(49.7 mg, 0.103 mmol) and (S)-tert-butyl pyrrolidin-3-ylcarbamate (144mg, 0.744 mmol), compound 44 (63 mg, 95%) as an off white solid,trifluoroacetic acid salt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₄H₃₀ClN₇O₃S requires: 532.18. Found 532.03.

HPLC Tr (min), purity %: 4.79, 99%.

Example 160 Preparation of Compound 45

To a solution of intermediate 26 (100 mg, 0.034 mmol) in DMF (5 ml) wasadded 2-amino-6-methyl benzoic acid (0.5 g, 3.3 mmol), and HATU (1.13 g,3.9 mmol). After stirring for 5 h at room temperature, volatiles wereremoved under reduced pressure. The crude residue was purified bypreparatory HPLC (5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier)to afford the coupled intermediate (44 mg, 33%) as a white solid. Thisintermediate was then reacted with methansulphonyl chloride (0.3 ml) inDMF (3 ml) at room temperature. After stirring for 0.5 h at roomtemperature, volatiles were removed under reduced pressure. The cruderesidue was purified by preparatory HPLC (5-100% MeCN/H₂O, 0.1%trifluoroacetic acid modifier) to afford the product 45 (44 mg, 47%) asa white solid.

LCMS (m/z) 468.15 [M+H]⁺

MW 467.6

Example 161 Preparation of Compound 46

To a solution of intermediate 26 (0.5 mmol) in DMF (1.5 ml) was addedthe carboxylate (0.1 g, 0.46 mmol) and HATU (0.132 g, 0.46 mmol). Afterstirring for 1 h at room temperature, volatiles were removed underreduced pressure. The crude residue was purified by preparatory HPLC(5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) to afford theproduct 46 (66 mg, 32%) as a white solid.

LCMS (m/z) 454.19 [M+H]⁺

MW 453.6

Example 162 Preparation of Compound 47

Following the procedure for compound 46, the product was obtained as awhite solid (5.4 mg, 12%).

LCMS (m/z) 522.15 [M+H]⁺

MW 521.6

Example 163 Preparation of Compound 48

Following the procedure for compound 46, the product was obtained as awhite solid (46.1 mg, 243%).

LCMS (m/z) 375.16 [M+H]⁺

MW 374.5

Example 164 Preparation of Compound 49

Following the procedure for compound 46, the product was obtained as awhite solid (100 mg, 43%).

LCMS (m/z) 389.17 [M+H]⁺

MW 388.5

Example 165 Preparation of Compound 50

To a solution of intermediate 30 (1 g, 3.68 mmol) in MeOH (5 ml) wasadded 3-hydroxyazetidine (2 g, 18.4 mmol). After stirring for 16 h atreflux, the volatiles were removed under reduced pressure. The cruderesidue was purified by preparatory HPLC (5-100%/MeCN/H₂O, 0.1%trifluoroacetic acid modifier) to afford the bis-adduct (92 mg, 9%) as awhite solid. This solid was dissolved in DMF (2.5 ml), NEt₃ (0.3 ml) and2-trifluromethyl-benzoyl chloride (0.2 ml) was added. After stirring for1 h at room temperature, the volatiles were removed under reducedpressure. The crude residue was purified by preparatory HPLC (5-100%MeCN/H₂O, 0.1% trifluoroacetic acid modifier) to afford the product 50(81 mg, 64%) as a white powder.

LCMS (m/z) 517.3 [M+H]⁺

MW 516.5

Example 166 Preparation of Compound 51

To a solution of intermediate 33 (0.14 g, 0.28 mmol) in MeCN (4 ml) wasadded the N-difluoroethyl-piperazine (0.062 g, 0.42 mmol). Afterstirring for 10 min at room temperature, volatiles were removed underreduced pressure. The crude material was dissolved in MeOH (3 ml),azetidine added (1 ml). After stirring for 16 h at room temperature,volatiles were removed under reduced pressure. The crude residue waspurified by preparatory HPLC (5-100% MeCN/H₂O, 0.1% trifluoroacetic acidmodifier) to afford the product 51 (133 mg, 74%) as a white powder.

LCMS (m/z) 637.26 [M+H]⁺

MW 637.2

Example 167 Preparation of Compound 52

To a solution of intermediate 4 (0.59 g, 2.21 mmol) in EtOH (2 ml) andHOAc (2 ml) was added 2,5-pentanedion (0.332 g). After stirring for 1 hat reflux, the volatiles were removed under reduced pressure. The cruderesidue was purified by silica gel chromatography using a gradient ofhexanes/ethyl acetate 1:0 to 0:1. The residue was dissolved in DCM (2ml) and TFA (2 ml) and stirred for 2 h. After removal of the solvent, tothe resulting amine (0.078 g, 0.34 mmol) in DMF (1.5 ml) was added thecarboxylate (0.102 g, 0.44 mmol), HATU (0.146 g, 0.51 mmol) and NEt₃(0.1 ml). After stirring for 1 h at room temperature, the volatiles wereremoved under reduced pressure. The crude residue was purified bypreparatory HPLC (5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier)to afford the product 52 (108 mg, 95%) as a white solid.

LCMS (m/z) 442.14 [M+H]⁺

MW 441.6

Example 168 Preparation of Compound 53

To a solution of intermediate 33 (0.2 g, 0.65 mmol) in MeCN (3 ml) wasadded the N-methyl-piperazine (0.071 g, 0.65 mmol) and aqueous sat.Na₂CO₃ to adjust the pH<8. After stirring for 1.5 h at room temperature,the volatiles were removed under reduced pressure. The crude materialwas dissolved in MeOH (3 ml) and N-Boc-amino-azetidine added (0.167 g).After stirring for 16 h at room temperature, the volatiles were removedunder reduced pressure. The residue was dissolved in DCM (2 ml) and TFA(2 ml) added and stirred for 2 h at room temperature. Volatiles wereremoved and the crude residue was purified by preparatory HPLC (5-100% VMeCN/H₂O, 0.1% trifluoroacetic acid modifier) to afford the product 53(49 mg, 12%) as a white powder.

LCMS (m/z) 602.18 [M+H]⁺

MW 602.2

Example 169 Preparation of Compound 54

To a solution of intermediate 33 (0.1 g, 0.2 mmol) in MeCN (3 ml) wasadded N-methyl-piperazine (0.114 g, 0.4 mmol). After stirring for 1.5 hat room temperature, volatiles were removed under reduced pressure. Thecrude material was dissolved in MeOH (3 ml), azetidine added (1 ml).After stirring for 16 h at room temperature, volatiles were removedunder reduced pressure. The residue was dissolved in THF (3 ml) andhydrazine (1 ml) and refluxed for 2 h at room temperature. Volatileswere removed and the crude residue was purified by preparatory HPLC(5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) to afford thecorresponding azetidine amide. The amide was subjected to LiOH (1.1 g)in water (5 ml) at reflux for 2 h to afford the product 54 (36 mg) as awhite powder after purification by preparatory HPLC (5-100% MeCN/H₂O,0.1% trifluoroacetic acid modifier)

LCMS (m/z) 615.15 [M−H]⁻

MW 617.1

Example 170 Preparation of Compound 55

To a solution of intermediate 30 (0.111 g, 0.4 mmol) in MeCN (5 ml) wasadded N-Boc-piperazine (0.152 g, 0.82 mmol). After stirring for 2 h atroom temperature, volatiles were removed under reduced pressure. Thecrude material was dissolved in MeOH (3 ml), azetidine added (1 ml).After stirring for 16 h at room temperature, the volatiles were removedunder reduced pressure. The crude residue was purified by preparatoryHPLC (5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) to afford theamine as a white solid. To the resulting amine (0.078 g, 0.34 mmol) inDMF (1.5 ml) was added 2-amino-5-chloro-benzoic acid (0.102 g, 0.44mmol), and HATU (0.146 g, 0.51 mmol) and NEt₃ (0.1 ml). After stirringfor 1 h at room temperature, volatiles were removed under reducedpressure. The crude residue was purified by preparatory HPLC(5-100%/MeCN/H₂O, 0.1% trifluoroacetic acid modifier) to afford theaniline (108 mg, 95%) as a white solid. This solid was dissolved inpyridine (2.5 ml) and the sulphonyl chloride added at room temperaturedrop wise until full conversion was observed. The volatiles were removedand the residue was dissolved in DCM (2 ml) and TFA (2 ml) added andstirred for 2 h at room temperature. The volatiles were removed and thecrude residue was purified by preparatory HPLC (5-100% MeCN/H₂O, 0.1%trifluoroacetic acid modifier) to afford the product 55 (49 mg, 12%) asa white powder.

LCMS (m/z) 641.24 [M+H]⁺

MW 641.1

Example 171 Preparation of Compound 56

To a solution of intermediate 33 (0.1 g, 0.2 mmol) in MeCN (3 ml) wasadded morpholine (0.2 mmol). After stirring for 1.5 h at roomtemperature, volatiles were removed under reduced pressure. The cruderesidue was purified by preparatory HPLC (5-100% MeCN/H₂0, 0.1%trifluoroacetic acid modifier) to afford the mono adduct. Thisintermediate (0.06 g) was dissolved in THF (2 ml), NMP (0.2 ml),Fe(acac)₃ (0.002 g) and 3-iodo-N-boc-azetidine (0.31 g) was added. Asolution of iPrMgCl (1.3 M, 1.7 ml) was added dropwise at −78° C. andthe solution warmed slowly to room temperature. The reaction wasquenched with aqueous saturated NH₄Cl. The volatiles were removed andthe crude residue was purified by preparatory HPLC (5-100% MeCN/H₂O,0.1% trifluoroacetic acid modifier) to afford the product 56 (16.1 mg)as a white powder.

LCMS (m/z) 574.19 [M+H]⁺

MW 574.1

Example 172 Preparation of Compound 57

Following the procedure for compound 56 with cylopentylmagnesiumbromide, the product 57 was obtained as a white solid (16 mg, 30%).

LCMS (m/z) 587.32 [M+H]⁺

MW 587.1

Example 173 Preparation of Compound 58

To a solution of intermediate 4 (0.94 g, 4.15 mmol) in HOAc (5 ml) wasadded 3-methyl-2,5-pentanedion (0.332 g). After stirring for 0.5 h atreflux, volatiles were removed under reduced pressure. The crude residuewas purified by silica gel chromatography using a gradient ofhexanes/ethyl acetate 1:0 to 0:1. The residue was dissolved in DCM (2ml) and TFA (2 ml) and stirred for 2 h. After removal of the solvent, tothe resulting amine (0.26 g) in DMF (1.5 ml) was added the5-fluoro-2-(methylsulfonamido)benzoic acid carboxylate (0.26 g), HATU(0.35 g) and NEt3 (0.1 ml). After stirring for 1 h at room temperature,the volatiles were removed under reduced pressure. The crude residue waspurified by preparatory HPLC (5-100% MeCN/H₂O, 0.1% trifluoroacetic acidmodifier) to afford the product 58 (101 mg, 72%) as a white solid.

LCMS (m/z) 460.12 [M+H]⁺

MW 459.5

Example 174 Preparation of Compound 59

To a solution of intermediate 35 (0.54 g, 1.4 mmol) in MeOH (2 ml) wasadded N-methyl-piperazine (2 ml) and stirred at room temperature for 4h. Volatiles were removed and the crude residue purified by silica gelchromatography using a gradient of hexanes/ethyl acetate. The residuewas dissolved in DCM (2 ml) and TFA (2 ml) and stirred for 2 h. Afterremoval of the solvent, to the resulting amine (0.09 g) in DMF (1.5 ml)was added the carboxylate (0.26 g), HATU (0.35 g) and NEt3 (0.1 ml).After stirring for 1 h at room temperature, volatiles were removed underreduced pressure. The crude residue was purified by preparatory HPLC(5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) to afford theproduct 59 (70.8 mg, 44%) as a white solid.

LCMS (m/z) 572.24 [M+H]⁺

MW 572.1

Example 175 Preparation of Compound 60

Intermediate 41 (43 mg, 0.109 mmol) was dissolved in DMF (500 uL) and2-(methylamino)ethanol (88 uL, 1.09 mmol) and TEA (304 uL, 2.18 mmol)were added. The material was stirred at 70° C. for 2 h and then cooledto room temperature. Dissolved with ethyl acetate and washed withsaturated aqueous sodium bicarbonate solution twice and saturatedaqueous sodium chloride solution. Dried organic extract over anhydroussodium sulfate and then concentrated under reduced pressure. Dissolvedmaterial in MeOH, added Pd/C and stirred under atm H₂(g) for 1 hr.Filtered through Celite and concentrated under reduced pressure. Mixed5-chloro-2-(methylsulfonamido)benzoic acid (28 mg, 0.109 mmol) with HATU(42 mg, 0.109 mmol) and dissolved in anhydrous DMF (300 uL). Stirred for1 hr. Dissolved hydrogenation product in anhydrous DMF (300 uL) andadded to the reaction. Added TEA (30 uL, 0.218 mmol). Stirred for 12hrs. Diluted with acetonitrile and purified with Prep HPLC to give titleproduct 60 (19 mg, 27% yield).

¹H NMR (400 MHz, CD₃OD): δ 7.49 (m, 3H), 6.72 (m, 1H), 6.08 (m, 1H),4.60 (m, 1H), 3.85 (m, 4H), 3.45-3.30 (m, 4H), 3.02 (m, 4H), 2.79 (s,3H), 2.40-2.05 (m, 2H), 1.73-1.50 (m, 4H).

LC/MS (m/z): 521.3 [M+H]⁺

Example 176 Preparation of Compound 61

To a solution of intermediate 42 (12 mg, 0.018 mmol) in dioxane (2.00mL) was added concentrated HCl (50 μL) and the reaction mixture wasstirred at room temperature overnight. Then the reaction mixture wasallowed to cool to room temperature and was concentrated under reducedpressure. The crude residue was purified by prep HPLC (0-100% CH₃CN/H₂O)to afford compound 61 (8 mg, 86%).

LCMS (m/z) 561.11 [M+H]⁺

MW 560.10

Example 177 Preparation of Compound 62

The title compound was prepared in 54% total yield according to thegeneral procedure for compound 61 (i.e. acylation step for thepreparation of intermediate 42 and Boc removal step for the preparationof compound 61) starting from intermediate 14 and benzoyl chloride.

LCMS (m/z) 558.12 [M+H]⁺

MW 557.07

Example 178 Preparation of Compound 63

The title compound was prepared in 14% total yield according to thegeneral procedure for compound 61 (i.e. acylation step for thepreparation of intermediate 42 and Boc removal step for the preparationof compound 61) starting from intermediate 14 and 2,2,2-trifluoroethylcarbonochloridate.

LCMS (m/z) 580.20 [M+H]⁺

MW 579.00

Example 179 Preparation of Compound 64

The title compound was prepared in 27% total yield according to thegeneral procedure for compound 61(i.e. acylation step for thepreparation of intermediate 42 and Boc removal step for the preparationof compound 61) starting from intermediate 14 and dimethylcarbamoylchloride.

LCMS (m/z) 525.05 [M+H]⁺

MW 524.05

Example 180 Preparation of Compound 65

The title compound was prepared in 47% total yield according to thegeneral procedure for compound 61(i.e. acylation step for thepreparation of intermediate 42 and Boc removal step for the preparationof compound 61) starting from intermediate 14 and difluoroaceticanhydride.

LCMS (m/z) 532.25 [M+H]⁺

MW 530.99

Example 181 Preparation of Compound 66

The title compound was prepared in 25% total yield according to thegeneral procedure for compounds 4-18 starting from intermediate 12 and4.6-dimethyl-pyridine-2-carboxylic acid.

LCMS (m/z) 434.27 [M+H]⁺

MW 433.55

Example 182 Preparation of Compound 67

The title compound was prepared in 68% total yield according to thegeneral procedure for compounds 4-18 starting from intermediate 12 and6-trifluoromethyl-pyridine-2-carboxylic acid.

LCMS (m/z) 473.85 [M+H]⁺

MW 472.49

Example 183 Preparation of Compound 68

Intermediate 46 (80 mg, 0.13 mmol) was dissolved in pyridine (2 ml), tothe solution was added isopropyl chloroformate (331 mg, 2.7 mmol) andNEt₃ (54 μl). The reaction was stirred at room temperature overnight andthe solvent was evaporated. The residue was purified with combi-flashcolumn chromatography (0-100/EtOAc/Hexane) to afford compound 68 (46 mg,50%/).

LCMS (m/z) 681.21 [M+H]⁺

MW 680.22

Example 184 Preparation of Compound 69

Compound 68 was dissolved in DCM (0.2 mL) and H₃PO₄ (5 μL) was added tothe solution. The reaction mixture was stirred at room temperature for 2h. The solvent was removed under reduced pressure and the residue waspurified with prep HPLC (0-100% CH₃CN/H₂O) to afford compound 69 (11 mg,50%).

LCMS (m/z) 581.26 [M+H]⁺

MW 580.11

Example 185 Preparation of Compound 70

Intermediate 47 (29 mg, 0.04 mmol) was dissolved in MeOH (2 mL), to thesolution was added azetidine (0.1 mL). The reaction was heated to 70° C.overnight. Then to the above reaction mixture was added concentrated HCl(0.1 mL) and heated at 70° C. overnight. The reaction was then quenchedwith NaHCO₃ (10 mL) and extracted with EtOAc (20 mL). The organicsolvent was removed under reduced pressure and the residue was purifiedwith prep HPLC (0-100% CH₃CN/H₂O) to afford compound 70 (6 mg, 24%).

LCMS (m/z) 587.20 [M+H]⁺

MW 586.14

Example 186 Preparation of Compound 71

The title compound was prepared in 27% yield according to the generalprocedure for synthesis of intermediate 47 and compound 70. Thusstarting from intermediate 33 the (R)-(+)-3-(Boc-amino)pyrrolidine wasinstalled according to the preparation of intermediate 47 and then theazetidine following the procedure of compound 70 to afford compound 71

LCMS (m/z) 573.31 [M+H]⁺

MW 572.11

Example 187 Preparation of Compound 72

The title compound was prepared in 30% yield according to the generalprocedure for synthesis of intermediate 47 and compound 70. Thusstarting from intermediate 33 the ((R)-(+)-3-(dimethylamino)pyrrolidinewas installed according to the preparation of intermediate 47 and thenthe azetidine following the procedure of compound 70 to afford compound72

LCMS (m/z) 600.92 [M+H]⁺

MW 600.16

Example 188 Preparation of Compound 73

Intermediate 50 (15 mg, 0.03 mmol) was dissolved in EtOH (2 mL). To thesolution was added 5% Pd (0.006 mmol) and TEA (17 ul). The reaction wasstirred at room temperature for 45 mins. Catalyst was filtered withcelite and solvent was concentrated under reduced pressure. The residuewas purified with Prep HPLC to yield compound 73 (14 mg, 100%).

LCMS (m/z) 467.75 [M+H]⁺

MW 466.58

Example 189 Preparation of Compound 74

Intermediate 109 (85 mg, 0.32 mmol) and HATU (152 mg, 0.4 mmol) weredissolved in DMF (3 ml). The reaction mixture was stirred at roomtemperature for 10 mins. To the above solution was added intermediate 26(50 mg, 0.2 mmol) and NEt₃ (50 μl). The reaction was stirred at roomtemperature for 30 mins and was quenched with brine (10 ml) and thenextracted with EtOAc (20 ml). The organic layer was washed with brinetwice (10 ml) and then was evaporated under reduced pressure. Theresidue was purified with combi-flash column chromatography (0-100%EtOAc/Hexane) to afford compound 74 (35 mg, 36%).

LCMS (m/z) 506.21 [M+H]⁺

MW 504.99

Example 190 Preparation of Compound 75

The title compound was prepared in 16% yield according to the procedurefor compound 74 starting from intermediate 26 and5-fluoro-2-methanesulfonamidobenzoic acid.

LCMS (m/z) 471.68 [M+H]⁺

MW 470.55

Example 191 Preparation of Compound 76

The title compound was prepared in 32% yield according to the procedurefor compound 74 starting from intermediate 26 and4-methyl-2-methanesulfonamidobenzoic acid.

LCMS (m/z) 467.82 [M+H]⁺

MW 466.58

Example 192 Preparation of Compound 77

The title compound was prepared in 68% yield according to the procedurefor compound 74 starting from intermediate 26 and5-chloro-2-aminobenzoic acid.

LCMS (m/z) 410.10 [M+H]⁺

MW 408.91

Example 193 Preparation of Compound 78

5-Chloro-2-methanesulfonamidobenzoic acid (18 mg, 0.073 mmol) and HATU(32 mg, 0.084 mmol) were dissolved in DMF (3 ml). The reaction mixturewas stirred at room temperature for 10 mins. To the above solution wasadded intermediate 51 (16 mg, 0.056 mmol) and NEt₃ (16 μl). The reactionwas stirred at room temperature for 30 mins and was quenched with brine(10 ml) and then extracted with EtOAc (20 ml). The organic layer waswashed with brine twice (10 ml) and then was evaporated under reducedpressure. The residue was purified with prep HPLC (0-100% CH₃CN/H₂O) toafford compound 78 (10 mg, 34%).

LCMS (m/z) 517.17 [M+H]⁺

MW 516.04

Example 194 Preparation of Compound 79

The title compound was prepared in 39% yield according to the procedurefor compound 78 starting from intermediate 51 and5-methyl-2-methanesulfonamidobenzoic acid.

LCMS (m/z) 497.28 [M+H]⁺

MW 496.62

Example 195 Preparation of Compound 80

Intermediate 37 (65 mg, 0.13 mmol) was dissolved in 1,4-dioxane (2 mL)and to the solution was added concentrated HCl (0.5 mL). The reactionmixture was stirred at room temperature for 1 h and then the solvent wasevaporated. The residue was then added to the DMF solution (3 mL) of5-ethyl-2-methanesulfonamidobenzoic acid (47 mg, 0.2 mmol) and HATU (95mg, 0.26 mmol) followed by addition of Net₃ (50 μl). The reaction wasstirred at room temperature for 30 mins and was quenched with brine (10ml) and then extracted with EtOAc (20 ml). The organic layer was washedwith brine twice (10 ml) and then was evaporated under reduced pressure.The residue was purified with combi-flash column chromatography (0-100%EtOAc/Hexane) to afford compound 80 (39 mg, 46%).

LCMS (m/z) 552.94 [M+H]⁺

MW 551.69

Example 196 Preparation of Compound 81

Intermediate 20 (1.08 g, 3.3 mmol) was dissolved in 1,4-dioxane (20 mL)and to the solution was added concentrated HCl (2 mL). The reactionmixture was stirred at room temperature for 1 h and then the solvent wasevaporated. The residue was then added to the DMF solution (20 mL) of5-methyl-2-methanesulfonamidobenzoic acid (1.1 g, 5 mmol) and HATU (2.5g, 6.6 mmol) followed by addition of NEt₃ (1.4 ml). The reaction wasstirred at room temperature for 30 mins and was quenched with brine (10ml) and then extracted with EtOAc (20 ml). The organic layer was washedwith brine twice (10 ml) and then was evaporated under reduced pressure.The residue was purified with combi-flash column chromatography (0-100%EtOAc/Hexane) to afford compound 81 (652 mg, 45%).

LCMS (m/z) 442.16 [M+H]⁺

MW 441.55

Example 197 Preparation of Compound 82

Intermediate 22 added to the DMF solution (2 mL) of5-methyl-2-aminobenzoic acid (35 mg, 0.19 mmol) and HATU (85 mg, 0.22mmol) followed by addition of NEt₃ (50 μl). The reaction was stirred atroom temperature for 30 mins and was added carbonate resin (50 mg) andwas stirred using shaker overnight. Then the resin was filtered and tothe filtrate was added acetyl chloride (50 μl). The solvent wasevaporated under reduced pressure. The residue was purified with prepHPLC (0-100% CH₃CN/H₂O) to afford compound 82 (54 mg, 59%).

LCMS (m/z) 419.68 [M+H]⁺

MW 418.52

Example 198 Preparation of Compound 83

The title compound was prepared in 26% yield according to the procedurefor compound 82 starting from intermediate 22 and2-amino-5-methyl-6-bromobenzoic acid.

LCMS (m/z) 498.35 [M+H]⁺

MW 497.42

Example 199 Preparation of Compound 84

Intermediate 28 (50 mg, 0.1 mmol) was dissolved in THF (2 mL) and to thesolution was added (R)-3-N-Boc-N-methylamino-pyrrolidine (200 mg) andDIPEA (0.3 mL). The reaction mixture was heated to 70° C. for 3 h. Tothe above solution was added concentrated HCl (0.2 mL) and heated at 70°C. for 30 mins. The solvent was removed under reduced pressure and theresidue was purified with prep HPLC (0-100%/o CH₃CN/H₂O) to affordcompound 84 (20 mg, 35%).

LCMS (m/z) 546.23 [M+H]⁺

MW 545.08

Example 200 Preparation of Compound 85

Intermediate 36 (66 mg, 0.16 mmol) was dissolved in 1,4-dioxane (2 mL)and to the solution was added concentrated HCl (0.2 mL). The reactionmixture was stirred at room temperature for 30 mins and then the solventwas evaporated. The residue was then added to the DMF solution (2 mL) of5-chloro-2-methanesulfonamidobenzoic acid (60 mg, 0.24 mmol) and HATU(122 mg, 0.32 mmol) followed by addition of NEt₃ (50 l). The reactionwas stirred at room temperature for 30 mins and was quenched with brine(10 ml) and then extracted with EtOAc (20 ml). The organic layer waswashed with brine twice (10 ml) and then was evaporated under reducedpressure. The residue was purified with prep HPLC (0-100% CH₃CN/H₂O) toafford compound 85 (39 mg, 52%).

LCMS (m/z) 474.12 [M+H]⁺

MW 472.98

Example 201 Preparation of Compound 86

Intermediate 16 (50 mg, 0.11 mmol) was dissolved in MeOH (2 mL) and tothe solution was added (S)-3-(Boc-amino)piperidine (65 mg, 0.33 mmol)and Net₃ (60 μl). The reaction mixture was heated to 70° C. for 3 h. Tothe above solution was added TFA (0.2 mL) and stirred at roomtemperature for 30 mins. The solvent was removed under reduced pressureand the residue was purified with prep HPLC (0-100% CH₃CN/H₂O) to affordcompound 86 (10 mg, 18%).

LCMS (m/z) 489.98 [M+H]⁺

MW 488.61

Example 202 Preparation of Compound 87

The title compound was prepared in 56% yield according to the procedureof the second step of Example 154 starting from intermediate 16 and3-N-Boc-aminoazetidine.

LCMS (m/z) 561.92 [M+H]+

MW 560.68

Example 203 Preparation of Compound 88

Intermediate 11 (40 mg, 0.083 mmol) was dissolved in MeOH (2 mL) and tothe solution was added (S)-3-(Boc-amino)piperidine (166 mg, 0.83 mmol).The reaction mixture was refluxed overnight. To the above solution wasadded concentrated HCl (0.2 mL) and stirred at room temperature for 30mins. The solvent was removed under reduced pressure and the residue waspurified with prep HPLC (0-100% CH₃CN/H₂O) to afford compound 88 (20 mg,45%).

LCMS (m/z) 546.21 [M+H]⁺

MW 545.08

Example 204 Preparation of Compound 89

To a solution of intermediate 32 (10.0 mg, 0.018 mmol) in MeOH (1.00 mL)was added 3-hydroxymethylazetidine (20 mg, 0.23 mmol) and triethylamine(55 μL, 0.4 mmol), and the reaction mixture was stirred at 70° C. After2 h, the reaction mixture was allowed to cool to room temperature andwas concentrated under reduced pressure. The crude residue was purifiedby preparatory HPLC (5-100% MeCN/H₂O) to afford compound 89 (10 mg, 91%)as a white solid.

LCMS (m/z) 604.35 [M+H]⁺

MW 603.12

Example 205 Preparation of Compound 90

The title compound was prepared in 92% yield according to the procedurefor compound 89 starting from intermediate 32 and pyrrolidine.

LCMS (m/z) 588.31 [M+H]⁺

MW 587.12

Example 206 Preparation of Compound 91

The title compound was prepared in 31% yield according to the procedurefor compound 89 starting from intermediate 32 and methylamine.

LCMS (m/z) 548.16 [M+H]⁺

MW 547.06

Example 207 Preparation of Compound 92

The title compound was prepared in 57% yield according to the procedurefor compound 89 starting from intermediate 32 and dimethylamine.

LCMS (m/z) 562.14 [M+H]⁺

MW 561.08

Example 208 Preparation of Compound 93

The title compound was prepared in 50% yield according to the procedurefor compound 89 starting from intermediate 32 and(R)-(−)-3-fluoropyrrolidine.

LCMS (m/z) 606.21 [M+H]⁺

MW 605.11

Example 209 Preparation of Compound 94

The title compound was prepared in 27% yield according to the procedurefor compound 88 starting from intermediate 32 and3-N-Boc-3-N-methylamino-pyrrolidine.

LCMS (m/z) 617.25 [M+H]⁺

MW 616.23

Example 210 Preparation of Compound 95

The title compound was prepared in 21% yield according to the procedurefor compound 88 starting from intermediate 32 and(R)-(−)-3-N-Boc-amino-pyrrolidine.

LCMS (m/z) 603.21 [M+H]⁺

MW 602.14

Example 211 Preparation of Compound 96

The title compound was prepared in 50% yield according to the procedurefor compound 89 starting from intermediate 32 and(S)-(−)-3-hydroxypyrrolidine.

LCMS (m/z) 604.23 [M+H]⁺

MW 603.12

Example 212 Preparation of Compound 97

Following the procedure of the second step of Example 154, beginningwith intermediate 11 (67 mg, 0.139 mmol) and azetidine-3-carbonitrile(57 mg, 0.695 mmol), compound 97 (10 mg, 14%) was synthesized.

LCMS m/z [M+H]⁺ C₂₄C₂₆ClN₇O₃S requires: 528.15. Found 528.15.

HPLC Tr (min), purity %: 6.87, 99%.

Example 213 Preparation of Compound 98

Following the procedure of the second step of Example 154, beginningwith intermediate 11 (60 mg, 0.124 mmol) and 3,3-difluoroazetidinehydrochloride (80 mg, 0.618 mmol), compound 98 (21 mg, 31%) wassynthesized.

LCMS m/z [M+H]⁺ C₂₃H₂₅ClF₂N₆O₃S requires: 539.14. Found 517.06.

HPLC Tr (min), purity %: 7.62, 99%.

Example 214 Preparation of Compound 99

Following the procedure of the second step of Example 154, beginningwith intermediate 11 (80 mg, 0.124 mmol) and methylazetidine-2-carboxylate (98 mg, 0.646 mmol) and heating at 80° C.,compound 99 (38 mg, 40%) was synthesized as a mixture of diastereomers.

LCMS m/z [M+H]⁺ C₂₅H₂₉ClN₆O₅S requires: 561.16. Found 561.37.

HPLC Tr (min), purity %: 7.04, 86%.

Example 215 Preparation of Compound 100

Following the synthesis of compound 27, beginning with intermediate 116(66 mg, 0.27 mmol) and intermediate 12 (28 mg, 0.07 mmol) andBoc-deprotection with HCl in step 2, compound 100 (10 mg, 25% over twosteps) was synthesized (˜1:1 mixture of diastereomers).

LCMS m/z [M+H]⁺ C₂₅H₃₂FN₇O₃S requires: 530.23. Found 530.42.

HPLC Tr (min), purity %: 4.74, 96%.

Example 216 Preparation of Compound 101

Following the synthesis of compound 27, beginning with2-(methylsulfonamido)-2-phenylacetic acid (90 mg, 0.39 mmol) andintermediate 12 (60 mg, 0.15 mmol) and Boc-deprotection with HCl in step2, compound 101 (8 mg, 10% over two steps) was synthesized (˜1:1 mixtureof diastereomers).

LCMS m/z [M+H]⁺ C₂₅H₃₃N₇O₃S requires: 512.24. Found 512.15.

HPLC Tr (min), purity %: 4.72, 97%.

Example 217 Preparation of Compound 102

Following the synthesis of compound 27, beginning with(S)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid (42 mg, 0.243mmol) and intermediate 12 (75 mg, 0.188 mmol) and Boc-deprotection withHCl in step 2, compound 102 (18 mg, 20% over two steps) was synthesized.

LCMS m/z [M+H]⁺ C₂₃H₃₃N₇O₃ requires: 456.26. Found 546.32.

HPLC Tr (min), purity %: 4.36, 99%.

Example 218 Preparation of Compound 103

Intermediate 56 (16 mg, 0.048 mmol) was dissolved in methanol (1 mL).HCl (4N in dioxane, 1 mL, 4 mmol) was added and reaction mixture wasstirred for 30 minutes. After concentrating under reduced pressure,residue was mixed with anhydrous DCM (2 mL) and TEA (0.020 mL, 0.144mol) and intermediate 102 (12 mg, 0.048 mmol) was added. After 30minutes, triethylamine was added (0.020 mL, 0.144 mmol). After 30minutes, additional methanol was added and then mixture was concentratedunder reduced pressure. Purification via prep HPLC (5-95% acetonitrilein water) gave compound 103 (12 mg, 56%).

¹H NMR (400 MHz, CD₃OD): δ 7.40-7.25 (m, 3H), 6.55-6.45 (m, 1H), 6.21(m, 1H), 2.95 (m, 7H), 2.60 (s, 3H), 2.45-2.34 (m, 5H), 2.11 (m, 1H),1.75-1.55 (m, 4H).

LC/MS (m/z): 443.2 [M+H]⁺

Example 219 Preparation of Compound 104

A solution of hydrogen chloride in dioxane (4N, 0.25 mL, 1.0 mmol) wasadded to a solution of intermediate 59 (5.8 mg, 0.0176 mmol) in 1 mL ofdioxane. After stirring overnight, LC/MS indicated full removal of Bocgroup. Reaction mixture was concentrated under reduced pressure anddried in-vacuo for two hours. To a solution of the resulting residuedissolved in 2 mL of anhydrous CH₂Cl₂ was added intermediate 120(5-chloro-2-(methylsulfonamido)benzoyl chloride) (5.1 mg, 0.020 mmol).After cooling to 0° C., triethylamine (7.0 μL, 0.049 mmol) was added,and resulting mixture was warmed to room temperature and stirredovernight. Reaction mixture was concentrated under reduced pressure andpurified by prep HPLC (15-100% Acetonitrile (with 0.1% trifluoroaceticacid) in water (with 0.1% trifluoroacetic acid)) to yield compound 104(3 mg, 37%) as a yellow solid, trifluoroacetic acid salt, afterlyophilization.

LCMS m/z [M+H]⁺ C₂₂H₂₅ClN₄O₃S requires: 461.13. Found 461.31.

¹H-NMR (DMSO, 400 MHz): δ 7.76 (s, 1H), 7.58 (m, 1H), 7.43-7.31 (m, 3H),6.93 (s, 1H), 6.20 (s, 1H), 3.65 (s, 1H), 3.16 (s, 3H), 3.14 (m, 1H),2.71 (s, 3H), 2.52 (s, 3H), 2.50 (m, 1H), 2.11 (m, 1H), 1.87 (m, 1H),1.71-1.45 (m, 4H).

HPLC Tr (min), purity %: 5.15, 99%

Example 220 Preparation of Compound 105

HATU (0.225 mg, 1.49 mmol) was added to a suspension of5-methyl-2-(methylsulfonamido)benzoic acid (0.15 g, 0.65 mmol) in DMF (2mL). The suspension was stirred for 30 minutes at room temperature.Intermediate 63 (0.125 g, 0.54 mmol) was dissolved in DMF (2 mL) andtriethylamine (0.1 mL, 9.88 mmol) was added. To this, was added the DMFsolution of 5-methyl-2-(methylsulfonamido)benzoic acid and HATU. Afterstirring for 2 h at room temperature, volatiles were removed underreduced pressure and the residue was dissolved in MeCN/water andpurified by preparatory HPLC (5-95% H₂O/MeCN, 0.1% TFA) to affordcompound 105 as a colorless powder (0.134 g, 57%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 8.95 (s, 1H), 7.31-7.19 (m, 3H), 6.61 (s,1H0, 6.51 (s, 1H), 6.40 (s, 1H), 6.04 (s, 1H), 4.90 (s, 0.5H), 4.46 (s,0.5H), 4.22-3.33 (m, 3H), 3.18 (m, 0.5H), 3.04 (m, 1H), 2.99 (s, 3H),2.63 (s, 3H), 2.48 (s, 3H), 2.19-1.29 (4H)

LCMS m/z [M+H]⁺ 441.14

HPLC Tr (min), purity %: 2.48, 98%

Example 221 Preparation of Compound 106

Triethylamine (0.050 mL, 0.363 mmol) was added to a mixture ofintermediate 65 (11.2 mg, 0.024 mmol) and azetidine hydrochloride (14mg, 0.150 mmol) in 2 mL of anhydrous methanol. Mixture was heated at 75°C. overnight. After cooling to room temperature, reaction mixture wasconcentrated under reduced pressure and residue was purified by prepHPLC (15-100% Acetonitrile (with 0.1% trifluoroacetic acid) in water(with 0.1% trifluoroacetic acid)) to yield compound 106 (5.8 mg, 40%) asa solid, trifluoroacetic acid salt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₂H₂₅ClN₆O₃S requires: 489.14. Found 489.05.

¹H-NMR (DMSO, 400 MHz): δ 9.19 (s, 1H), 8.66 (m, 1H), 7.55-7.36 (m, 3H),6.32 (s, 1H), 5.98 (m, 1H), 3.88 (m, 2H), 3.57 (m, 1H), 3.22 (m, 2H),3.04 (s, 3H), 2.89 (t, J=12.4 Hz, 2H), 2.37 (m, 1H), 2.06-1.82 (m, 2H),1.74-1.41 (m, 4H).

HPLC Tr (min), purity %: 5.49, 85%

Example 222 Preparation of Compound 107

Trifluoroacetic acid (0.45 mL, 5.78 mmol) was added to a solution ofintermediate 68 (65 mg, 0.10 mmol) in 6 mL of dichloromethane at roomtemperature. After 150 minutes, the reaction mixture was concentratedunder reduced pressure and dried in-vacuo for twenty four hours to yieldcompound 107 (66 mg, 99%) as a brown solid, trifluoroacetic acid salt.

LCMS m/z [M+H]C₂₄H₃₀ClN₇O₃S requires: 532.18. Found 532.01.

¹H-NMR (DMSO, 400 MHz): δ 10.1 (s, 1H), 8.05 (s, 3H), 7.85 (s, 1H),7.61-7.40 (m, 3H), 5.99 (m, 1H), 4.76 (m, 1H), 4.30-3.45 (m, 3H), 3.18(m, 1H), 2.99 (s, 3H), 2.41 (s, 3H), 2.37-2.17 (m, 3H), 2.04-1.82 (m,3H), 1.71-1.21 (m, 5H).

HPLC Tr (min), purity %: 4.37, 97%

Example 223 Preparation of Compound 108

A mixture of intermediate 72 (5.8 mg, 0.012 mmol) and (S)-tert-butylpyrrolidin-3-ylcarbamate (73 mg, 0.28 mmol) and triethylamine (0.030 mL,0.21 mmol) in 2.5 mL of methanol was heated at 75° C. for 120 hours.LC/MS analysis showed ˜12% conversion to desired product, inseparablefrom intermediate 72. The reaction mixture was concentrated underreduced pressure to yield a residue that was dissolved in 2 mL of CH₂Cl₂and trifluoroacetic acid (0.100 mL, 1.30 mmol) was added. After 1 hour,the reaction mixture was concentrated under reduced pressure and residuewas purified by prep HPLC (15-100% Acetonitrile (with 0.1%trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) toyield compound 108 (0.8 mg, 10%) as a yellow film, trifluoroacetic acidsalt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₄H₃₀ClN₇O₃S requires: 532.18. Found 532.02.

HPLC Tr (min), purity %: 4.33, 99%

Example 224 Preparation of Compound 109

To a solution of intermediate 77 (20 mg, 0.06 mmol) and triethylamine(25 l, 0.18 mmol) in dichloromethane (0.5 mL) was added intermediate 120(5-chloro-2-(methylsulfonamido)benzoyl chloride) (16 mg, 0.06 mmol) atroom temperature under an argon atmosphere. After 2 h, the reactionmixture was directly purified via SiO₂ column chromatography (4 g SiO₂Combiflash HP Gold Column, 0-100% ethyl acetate/hexanes) to affordcompound 109 (8.2 mg, 25%) as a colorless solid.

¹H NMR (CD₃OD, 400 MHz): δ 7.53-7.47 (m, 1H), 7.46-7.39 (m, 3H), 5.85(s, 1H), 4.39-4.25 (m, 5H), 4.10 (t, J=7.8 Hz, 4H), 3.09 (s, 3H), 2.47(quint, J=7.7 Hz, 2H), 2.39 (quint, J=7.5 Hz, 2H), 2.05-1.87 (m, 1H),1.78-1.53 (m, 3H), 1.46-1.24 (m, 4H)

HPLC t_(R) (min), purity %: 3.55, 85%.

LCMS (ESI) m/z 545.19 [M+H]⁺, t_(R)=1.97 min.

R_(f)=0.50 (5% methanol/dichloromethane).

Example 225 Preparation of Compound 110

HATU (23 mg, 0.06 mmol) and 5-methyl-2-(methylsulfonamide)benzoic acid(11 mg, 0.05 mmol) were dissolved in anhydrous DMF (1 mL). Afteractivation for 1 hour, intermediate 80 (7 mg, 0.03 mmol) andtriethylamine (0.1 mL, 0.72 mmol) were added. The reaction was stirredunder nitrogen for 2 hours. Solvents were removed under reducedpressure. The residue was purified with prep HPLC (0-100% acetonitrilein water) to provide compound 110 (2 mg, 15%).

¹H-NMR (CD₃OD, 400 MHz): δ 7.61 (s, 1H), 7.46 (bs, 1H), 7.34 (d, J=12Hz, 1H), 7.22-7.19 (m, 1H), 6.80 (bs, 1H), 6.10 (bs, 1H), 2.89-2.81 (m,2H), 2.65 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 1.93 (bs, 1H), 1.67-1.64(m, 3H), 1.46 (bs, 2H), 1.19 (s, 3H).

LCMS m/z [M+H]⁺ C₂₂H₂₇NsO₃S requires: 442.55. Found 442.13

HPLC Tr (min), purity %: 3.35, 98%

Example 226 Preparation of Compound 111

HATU (9.5 mg, 0.038 mmol) and 5-chloro-2-(methylsulfonamide)benzoic acid(7.8 mg, 0.03 mmol) were dissolved in anhydrous DMF (1 mL). Afteractivation for 1 hour, intermediate 83 (5 mg, 0.019 mmol) andtriethylamine (0.1 mL, 0.718 mmol) were added. The reaction was stirredunder nitrogen for 2 hours. Solvents were removed by reduced pressureand the residue was purified with prep HPLC (0-100% acetonitrile inwater) to provide compound 111 (3 mg, 32%).

¹H-NMR (CD₃OD, 400 MHz): δ 7.94 (d, J=1.8 Hz, 1H), 7.47 (d, J=6.6 Hz,2H), 7.42-7.36 (m, 2H), 7.30-7.26 (m, 2H), 5.99 (d, J=7.2 Hz, 1H), 3.94(t, J=5.4 Hz, 4H), 2.96-2.95 (m, 3H), 2.85 (s, 3H), 2.30 (quintet, J=5.7Hz, 2H), 2.29 (s, 3H), 2.09-1.98 (m, 2H), 1.59-1.48 (m, 4H)

LCMS m/z [M+H]⁺ C₂₃H₂₆ClN₅O₃S requires: 488.00. Found 488.00

HPLC Tr (min), purity %: 2.32, 98%.

Example 227 Preparation of Compound 112

HATU (32 mg, 0.084 mmol) and 5-methyl-2-(methylsulfonamide)benzoic acid(15.5 mg, 0.068 mmol) were dissolved in anhydrous DMF (2 mL). Afteractivation for 1 hour, intermediate 85 (15 mg, 0.056 mmol) andtriethylamine (0.1 mL, 0.718 mmol) were added. The reaction mixture wasstirred under nitrogen for 2 hours. Solvents were removed by underreduced pressure and the residue was purified with prep HPLC (0-100%acetonitrile in water) to provide compound 112 (16 mg, 57%).

¹H-NMR (CD₃OD, 400 MHz): δ 7.60 (d, J=6.0 Hz, 1H), 7.31-7.26 (m, 1H),7.23-7.09 (m, 2H), 6.33 (bs, 1H), 3.54-3.51 (m, 2H), 3.16-3.12 (m, 2H),2.99 (s, 3H), 2.77 (s, 3H), 2.38 (s, 3H), 2.32 (s, 3H), 1.88 (bs, 2H),1.55 (bs, 2H).

LCMS m/z [M+H]⁺ C₂₂H₂₇N₅O₃S requires: 442.18. Found 442.12

HPLC Tr (min), purity %: 2.26, 98%.

Example 228 Preparation of Compound 113

To a solution of intermediate 86 (67 mg, 0.20 mmol) in dichloromethane(2 mL) was added trifluoroacetic acid (2 mL) at room temperature. After1 h, the resulting mixture was concentrated under reduced pressure. Tothe residue was added 5-chloro-2-(methylsulfonamido)benzoic acid (54.9mg, 0.22 mmol), HATU (83.7 mg, 0.22 mmol) followed by acetonitrile (1mL) and diisopropylethylamine (139 μL, 0.80 mmol), and the resultingmixture was stirred at room temperature. After 16 h, the reactionmixture was partitioned between ethyl acetate (50 mL) and saturatedaqueous sodium bicarbonate solution (50 mL). The phases were separated,and the organic layer was washed with saturated sodium chloride solution(2×50 mL). The organic layer was dried over Na₂SO₄, and was concentratedunder reduced pressure. The crude residue was purified by preparatoryHPLC (5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) to affordcompound 113 (25.8 mg, 28%) as a tan solid.

LCMS (ESI) m/z 463.10 [M+H], t_(R)=2.35 min.

¹H NMR (CD₃OD, 400 MHz): δ 7.71-7.32 (m, 3H), 7.11 (s, 1H), 6.18 (s,1H), 3.59-3.37 (m, 2H), 3.07 (s, 3H), 2.84 (s, 3H), 2.65 (s, 3H),2.15-2.01 (m, 1H), 1.84-1.37 (m, 5H).

HPLC t_(R) (min), purity %: 4.03, 95%.

R_(f)=0.55 (ethyl acetate).

Example 229 Preparation of Compound 114

Following the procedure for synthesis of compound 107, but beginningwith intermediate 88 (21 mg, 0.034 mmol), compound 114 (20 mg, 99%) wasrecovered as a light yellow film, trifluoroacetic acid salt.

LCMS m/z [M+H]⁺ C₂₃H₃₁N₇O₃S₂ requires: 518.19. Found 518.19.

¹H-NMR (DMSO, 400 MHz): δ 10.4 (s, 1H), 8.01 (s, 3H), 7.94 (m, 1H), 7.73(s, 1H), 6.89 (s, 1H), 6.51 (br s, 2H), 3.89 (m, 2H), 3.68 (m, 3H), 3.07(s, 3H), 2.65 (m, 1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.35-2.21 (m, 3H),1.97 (m, 1H), 1.85 (m, 1H), 1.68-1.38 (m, 3H).

HPLC Tr (min), purity %: 4.36, 98%

Example 230 Preparation of Compound 115

Following the procedure for synthesis of compound 107, but beginningwith intermediate 117 (30 mg, 0.049 mmol), compound 115 (27 mg, 88%) wasrecovered as a light yellow-brown film, trifluoroacetic acid salt.

LCMS m/z [M+H]⁺ C₂₅H₃₃N₇O₃S requires: 512.24. Found 512.27.

¹H-NMR (MeOD, 400 MHz): δ 8.28 (s, 1H), 7.86 (s, 1H), 7.41-7.22 (m, 2H),7.33 (s, 2H), 6.15 (s, 1H), 4.00 (m, 3H), 3.82 (m, 2H), 3.58 (m, 1H),3.17 (m, 1H), 3.02 (s, 3H), 3.00 (m, 1H), 2.66 (s, 3H), 2.58-2.32 (m,4H), 2.40 (s, 3H), 2.19 (m, 2H), 1.85 (m, 1H), 1.78-1.58 (m, 2H).

HPLC Tr (min), purity %: 4.30, 94%

Example 231 Preparation of Compound 116

Following the procedure used to prepare compound 107, but beginning withintermediate 89 (11 mg, 0.049 mmol), compound 116 (10.6 mg, 94%) wasrecovered as a light yellow film, trifluoroacetic acid salt.

LCMS m/z [M+H]⁺ C₂₅H₃₂BrN₇O₃S requires: 590.15. Found 590.48.

HPLC Tr (min), purity %: 4.84, 95%

Example 232 Preparation of Compound 117

Intermediate 65 (20 mg, 0.043 mmol) and (S)-tert-butylpyrrolidin-3-ylcarbamate (240 mg, 1.29 mmol) were mixed in 2 mL ofanhydrous methanol. Mixture was heated at 75° C. for 3 days. Aftercooling to room temperature, reaction mixture was concentrated underreduced pressure and residue was dissolved in dichloromethane (1 mL) andTFA (0.1 mL, 1.30 mmol) was added to the solution. The reaction mixturewas stirred for two hours and solvent was concentrated under reducedpressure. The residue was purified by prep HPLC (15-100% Acetonitrile(with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroaceticacid)) to yield compound 117 (10 mg, 45%) as a solid, trifluoroaceticacid salt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₃H₂₈ClN₇O₃S requires: 518.17. Found 518.22.

¹H-NMR (DMSO, 400 MHz): δ 8.01 (d, J=9.2 Hz, 1H), 7.83 (s, 1H),7.49-7.37 (m, 3H), 6.91 (bs, 1H), 6.04 (s, 1H), 3.99 (s, 2H), 3.75-3.66(m, 2H), 3.60 (m, 2H), 2.89 (s, 3H), 2.43-2.40 (m, 2H), 2.31-2.13 (m,2H), 1.89 (bs, 2H), 1.68 (m, 2H), 1.49 (s, 2H).

HPLC Tr (min), purity %: 2.26, 85%

Example 233 Preparation of Compound 118

Intermediate 65 (20 mg, 0.043 mmol) and(3S,4R)-4-hydroxypyrrolidine-3-carbonitrile (120 mg, 1.08 mmol) weremixed in 2 mL of anhydrous methanol. To the mixture was addedtriethylamine (0.12 mL, 0.868 mmol) and the reaction mixture was heatedat 75° C. for 5 days. After cooling to room temperature, reactionmixture was concentrated under reduced pressure and residue was purifiedby prep HPLC (15-100% Acetonitrile (with 0.1% trifluoroacetic acid) inwater (with 0.1% trifluoroacetic acid)) to yield compound 118 (10 mg,45%) as a solid, trifluoroacetic acid salt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₄H₂₆ClN₇O₄S requires: 544.15. Found 544.21.

¹H-NMR (DMSO, 400 MHz): δ 8.20 (s, 1H), 8.15 (s, 1H), 7.52-7.46 (m, 4H),6.15 (s, 1H), 4.10-3.95 (m, 2H), 3.81-3.62 (m, 4H), 3.61-3.45 (m, 4H),3.02 (s, 3H), 1.81 (bs, 2H), 1.66 (bs, 3H).

HPLC Tr (min), purity %: 2.07, 90%

Example 234 Preparation of Compound 119

Intermediate 91 (12 mg, 0.034 mmol) and (S)-tert-butylpyrrolidin-3-ylcarbamate (375 mg, 2.04 mmol) were mixed in 2 mL ofanhydrous methanol. Mixture was heated at 75° C. for 5 days. Aftercooling to room temperature, reaction mixture was concentrated underreduced pressure and residue was dissolved in dichloromethane (1 mL) andTFA (0.1 mL, 1.30 mmol) was added to the solution. The reaction mixturewas stirred for two hours and solvent was concentrated under reducedpressure. The residue was purified by prep HPLC (15-100% Acetonitrile(with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroaceticacid)) to yield compound 119 (8 mg, 56%) as a solid, trifluoroaceticacid salt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₂H₂₇N₇O requires: 406.23. Found 406.30.

¹H-NMR (DMSO, 400 MHz): δ 8.31 (s, 1H), 8.09-8.04 (m, 1H), 7.96-7.88 (m,1H), 7.61-7.30 (m, 3H), 6.22 (s, 1H), 4.12 (s, 1H), 3.95-3.90 (m, 1H),3.85-3.66 (m, 4H), 2.60 (s, 3H), 2.55-2.42 (m, 3H), 2.15-2.00 (m, 2H),1.83-1.60 (m, 5H).

HPLC Tr (min), purity %: 1.52, 90%

Example 235 Preparation of Compound 120

Intermediate 65 (20 mg, 0.043 mmol) and 3-hydroxyazetidine (46 mg, 0.43mmol) were mixed in 2 mL of anhydrous methanol. To the solution wasadded triethylamine (0.24 mL, 1.72 mmol). Mixture was heated at 75° C.for 2 days. After cooling to room temperature, reaction mixture wasconcentrated under reduced pressure and the residue was purified by prepHPLC (15-100% Acetonitrile (with 0.1% trifluoroacetic acid) in water(with 0.1% trifluoroacetic acid)) to yield compound 120 (7 mg, 47%) as asolid, trifluoroacetic acid salt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₂H₂₅ClN₆O₄S requires: 505.13. Found 505.19.

¹H-NMR (DMSO, 400 MHz): δ 7.95 (s, 1H), 7.76-7.44 (m, 1H), 7.33 (m, 3H),6.59-6.50 (m, 1H), 6.03 (s, 1H), 4.64-4.59 (m, 2H), 4.23-4.19 (m, 2H),3.78-3.75 (m, 2H), 2.90 (s, 3H), 2.43-2.16 (m, 2H), 1.94-1.44 (m, 6H).

HPLC Tr (min), purity %: 2.02, 95%

Example 236 Preparation of Compound 121

Intermediate 92 (14 mg, 0.036 mmol) and (S)-tert-butylpyrrolidin-3-ylcarbamate (375 mg, 2.04 mmol) were mixed in 2 mL ofanhydrous methanol. Mixture was heated at 75° C. for 5 days. Aftercooling to room temperature, reaction mixture was concentrated underreduced pressure and residue was dissolved in dichloromethane (1 mL) andTFA (0.1 mL, 1.30 mmol) was added to the solution. The reaction mixturewas stirred for two hours and solvent was concentrated under reducedpressure. The residue was purified by prep HPLC (15-100% Acetonitrile(with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroaceticacid)) to yield compound 121 (12 mg, 73%) as a solid, trifluoroaceticacid salt, after lyophilization.

LCMS m/z [M+H]⁺ C₂₃H₂₇ClN₆O requires: 439.19. Found 439.30.

¹H-NMR (DMSO, 400 MHz): δ 7.90-7.61 (m, 2H), 7.38-7.19 (m, 3H),7.02-6.10 (m, 1H), 6.10 (s, 1H), 4.00 (s, 1H), 3.78-3.59 (m, 5H), 2.28(s, 3H), 2.20-2.05 (m, 2H), 1.93-1.80 (m, 2H), 1.70-1.50 (m, 6H).

HPLC Tr (min), purity %: 1.71, 90%

Example 237 Preparation of Compound 122

PyBOP (223 mg, 0.78 mmol) was added to a suspension of2-(methylsulfonamido)benzoic acid (150 mg, 0.69 mmol) in 2 mL of DMF atroom temperature. After 30 minutes, intermediate 94 (150 mg, 0.65 mmol)was added, followed by triethylamine until pH was >9. After stirringunder nitrogen for 3 hours, volatiles were removed under reducedpressure. The residue was dissolved in MeCN/water and purified bypreparatory HPLC (5-95% H₂O/McCN, 0.1% TFA) to afford compound 122 (154mg, 54%) as a colorless powder.

¹H NMR (CDCl₃, 400 MHz): δ 9.07 (s, 1H), 7.31-7.23 (m, 5H), 6.85 (s,1H), 4.93 (s, 1H), 3.31 (m, 5H), 2.98 (s, 3H), 2.29 (s, 3H), 2.08-1.53(m, 6H).

LCMS m/z [M+H]⁺ 441.12

HPLC Tr (min), purity %: 2.11, 98%

Antiviral Activity

Another aspect of the invention relates to methods of inhibiting viralinfections, comprising the step of treating a sample or subjectsuspected of needing such inhibition with a composition of theinvention.

Within the context of the invention samples suspected of containing avirus include natural or man-made materials such as living organisms;tissue or cell cultures; biological samples such as biological materialsamples (blood, serum, urine, cerebrospinal fluid, tears, sputum,saliva, tissue samples, and the like); laboratory samples; food, water,or air samples; bioproduct samples such as extracts of cells,particularly recombinant cells synthesizing a desired glycoprotein; andthe like. Typically the sample will be suspected of containing anorganism which induces a viral infection, frequently a pathogenicorganism such as a tumor virus. Samples can be contained in any mediumincluding water and organic solvent\water mixtures. Samples includeliving organisms such as humans, and manmade materials such as cellcultures.

If desired, the anti-virus activity of a compound of the invention afterapplication of the composition can be observed by any method includingdirect and indirect methods of detecting such activity. Quantitative,qualitative, and semi-quantitative methods of determining such activityare all contemplated. Typically one of the screening methods describedabove are applied, however, any other method such as observation of thephysiological properties of a living organism are also applicable.

The antiviral activity of a compound of the invention can be measuredusing standard screening protocols that are known. For example, theantiviral activity of a compound can be measured using the followinggeneral protocols.

Respiratory Syncytial Virus (RSV) Antiviral Activity and CytotoxicityAssays Anti-RSV Activity

Antiviral activity against RSV was determined using an in vitrocytoprotection assay in Hep2 cells. In this assay, compounds inhibitingthe virus replication exhibit cytoprotective effect against thevirus-induced cell killing were quantified using a cell viabilityreagent. The method used was similar to methods previously described inpublished literature (Chapman et al., Antimicrob Agents Chemother. 2007,51(9):3346-53.) Hep2 cells were obtained from ATCC (Manassas, Va.) andmaintained in MEM media supplemented with 10% fetal bovine serum andpenicillin/streptomycin. Cells were passaged twice a week and kept atsubconfluent stage. Commercial stock of RSV strain A2 (AdvancedBiotechnologics, Columbia, Md.) was titered before compound testing todetermine the appropriate dilution of the virus stock that generateddesirable cytopathic effect in Hep2 cells.

For antiviral tests, Hep2 cells were seeded into 96-well plates 24 hoursbefore the assay at a density of 3,000 cells/well. On a separate 96wellplate, compounds to be tested were serially diluted in cell culturemedia. Eight concentrations in 3-fold serial dilution increments wereprepared for each tested compound and 100 μL/well of each dilution wastransferred in duplicate onto plates with seeded Hep2 cells.Subsequently, appropriate dilution of virus stock previously determinedby titration was prepared in cell culture media and 100 uL/well wasadded to test plates containing cells and serially diluted compounds.Each plate included three wells of infected untreated cells and threewells of uninfected cells that served as 0% and 100% virus inhibitioncontrol, respectively. Following the infection with RSV, testing plateswere incubated for 4 days in a tissue culture incubator. After theincubation, RSV-induced cytopathic effect was determined using a CellTiterGlo reagent (Promega, Madison, Wis.) followed by a luminescenceread-out. The percentage inhibition was calculated for each testedconcentration relative to the 0% and 100% inhibition controls and theEC50 value for each compound was determined by non-linear regression asa concentration inhibiting the RSV-induced cytopathic effect by 50%.Ribavirin (purchased from Sigma, St. Louis, Mo.) was used as a positivecontrol for antiviral activity.

Compounds were also tested for antiviral activity against RSV in Hep2cells using a 384 well format. Compounds were diluted in DMSO using a10-step serial dilution in 3-fold increments via automation in 4adjacent replicates each. Eight compounds were tested per dilutionplate. 0.4 uL of diluted compounds were then stamped via Biomek into384-well plates (Nunc 142761 or 164730 w/lid 264616) containing 20 μL ofmedia (Mediatech Inc. MEM supplemented with Glutamine, 10% FBS andPen/Strep). DMSO and a suitable positive control compound, such as 80 μMGS-329467 or 10 μM 427346 was used for the 100% and 0% cell killingcontrols, respectively.

Hep2 cells (1.0×10⁵ cells/ml) were prepared as above in batch to atleast 40 mls excess of the number of sample plates (8 mls cell mix perplate) and infected with vendor supplied (ABI) RSV strain A2 to arriveat an MOI of 1:1000 (virus:cell #) or 1:3000 (vol virus: cell vol).Immediately after addition of virus, the RSV infected Hep2 cellsuspension was added to each stamped 384-well plate at 20 μl per wellusing a uFlow dispenser, giving a final volume of 40 μL/well, each with2000 infected cells. The plates were then incubated for 5 days at 37° C.and 5% CO₂. Following incubation, the plates were equilibrated to roomtemperature in a biosafety cabinet hood for 1.5 hrs and 40 μL ofCell-Titer Glo viability reagent (Promega) was added to each well viauFlow. Following a10-20 minute incubation, the plates were read using anEnVision or Victor Luminescence plate reader (Perkin-Elmer). The datawas then uploaded and analyzed on the Bioinformatics portal under theRSV Cell Infectivity and 8-plate EC50-Hep2-384 or 8-plateEC50-Hep2-Envision protocols.

Multiple point data generated in the assay was analysed using PipelinePilot (Accelrys, Inc., Version 7.0) to generate a dose response curvebased on least squares fit to a 4-parameter curve. The generated formulafor the curve was then used to calculate the % inhibition at a givenconcentration. The % inhibition reported in the table was then adjustedbased on the normalization of the bottom and top of the curve %inhibition values to 0% and 100% respectively.

Representative activities for compounds disclosed herein againstRSV-induced cytopathic effects are shown in the Table below.

Compound Percent inhibition formula at 0.5 μM 1 95 2 97 3 100 4 100 5100 6 100 7 100 8 100 9 100 10 100 11 100 12 100 13 98 14 97 15 92 16100 17 96 18 100 19 100 20 100 21 100 22 100 23 100 24 91 25 97 26 97 27100 28 100 29 90 30 91 31 86 32 85 33 100 34 100 35 100 36 100 37 100 38100 39 99 40 100 41 100 42 100 43 100 44 100 45 100 46 97 47 99 48 93 4994 50 100 51 100 52 99 53 99 54 98 55 98 56 93 57 93 58 89 59 92 60 8761 100 62 100 63 100 64 100 65 100 66 100 67 99 68 100 69 99 70 100 71100 72 100 73 100 74 97 75 100 76 99 77 94 78 99 79 100 80 99 81 100 8297 83 100 84 95 85 86 86 84 87 89 88 89 89 90 90 100 91 91 92 98 93 5694 89 95 99 96 90 97 97 98 100 99 100 100 100 101 100 102 99 103 27 1043 105 96 106 100 107 100 108 100 109 64 110 60 111 56 112 5 113 16 114100 115 100 116 100 117 100 118 100 119 83 120 100 121 100 122 15

Cytotoxicity

Cytotoxicity of tested compounds was determined in uninfected Hep2 cellsin parallel with the antiviral activity using the cell viability reagentin a similar fashion as described before for other cell types (Cihlar etal., Antimicrob Agents Chemother. 2008, 52(2):655-65.). The sameprotocol as for the determination of antiviral activity was used for themeasurement of compound cytotoxicity except that the cells were notinfected with RSV. Instead, fresh cell culture media (100 uL/well)without the virus was added to tested plates with cells and predilutedcompounds. Cells were then incubated for 4 days followed by a cellviability test using CellTiter Glo reagent and a luminescence read-out.Untreated cell and cells treated with 50 ug/mL puromycin (Sigma, St.Louis, Mo.) were used as 100% and 0% cell viability control,respectively. The percent of cell viability was calculated for eachtested compound concentration relative to the 0% and 100% controls andthe CC50 value was determined by non-linear regression as a compoundconcentration reducing the cell viability by 50%.

To test for compound cytotoxicity in Hep2 cells using a 384 well format,compounds were diluted in DMSO using a 10-step serial dilution in 3-foldincrements via automation in 4 adjacent replicates each. Eight compoundswere tested per dilution plate. 0.4 uL of diluted compounds were thenstamped via Biomek into 384-well plates (Nunc 142761 or 164730 w/lid264616) containing 20IpL of media (Mediatech Inc. MEM supplemented withGlutamine, 10% FBS and Pen/Strep). 50 μg/mL puromycin and DMSO were usedfor the 100% and 0% cytotoxicity controls, respectively.

Hep2 cells (1.0×10⁵ cells/ml) were added to each stamped plate at 20 ulper well to give a total of 2000 cells/well and a final volume of 40dL/well. Usually, the cells were batch prediluted to 1.0×10⁵ cells/mL inexcess of the number of sample plates and added at 20 ul per well intoeach assay plate using a uFlow dispenser. The plates were then incubatedfor 4 days at 37° C. and 5% CO₂. Following incubation, the plates wereequilibrated to room temperature in a biosafety cabinet hood for 1.5 hrsand 40 μL of Cell-Titer Glo viability reagent (Promega) was added toeach well via uFlow. Following a 10-20 minute incubation, the plateswere read using an EnVision or Victor Luminescence plate reader(Perkin-Elmer). The data was then uploaded and analyzed on theBioinformatics portal (Pipeline Pilot) under the Cytotoxicity assayusing the 8-plate CC50-Hep2 or 8-plate CC50-Hep2 Envision protocols.

All publications, patents, and patent documents cited herein above areincorporated by reference herein, as though individually incorporated byreference. The invention has been described with reference to variousspecific and preferred embodiments and techniques. However, one skilledin the art will understand that many variations and modifications may bemade while remaining within the spirit and scope of the invention.

1. Method of treating a Pneumovirinae virus infection in a human in needthereof comprising administering to the human a therapeuticallyeffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein: a) Y¹ is N, NHor CH, Y² is C, Y² is N or CR^(8′), Y⁴ is N or C and Y⁵ is N, NR² orCR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ are independently N,NH or NR^(2′); or b) Y¹ is N, NH or CH, Y² is N or C, Y³ is N orCR^(8′), Y⁴ is N or C, and Y⁵ is N or NR^(2′), wherein at least two ofY¹, Y², Y³, Y⁴ and Y⁵ are independently N, NH or NR^(2′); or c) Y¹ is N,NH or CH, Y² is N or C, Y³ is CR^(8′), Y⁴ is N or C, and Y⁵ is N,NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently N, NH or NR^(2′); the dashed bonds ---- are selected fromsingle bonds and double bonds so as to provide an aromatic ring system;A is —(CR⁴R^(4′))_(n); n is 3, 4, 5 or 6; each p is 1 or 2; Ar is aC₂-C₂₀ heterocyclyl group or a C₆-C₂₀ aryl group, wherein the C₂-C₂₀heterocyclyl group or the C₆-C₂₀ aryl group is optionally substitutedwith 1 to 5 R⁶; X is —C(R¹³)(R¹⁴)—, —N(CH₂R¹⁴)— or —NH—, or X is absent;R¹ is H, —OR¹¹, NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹²,N₃, CN, NO₂, —SR¹¹, —S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═ONR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R² is H, CN, NO₂,halogen or (C₁-C₈)alkyl; R² is H or (C₁-C₈)alkyl; R³ is H, —OR¹¹,NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(ONR¹¹R¹², N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R^(a), —C(═O)OR¹¹,—C(═ONR¹¹R¹², —C(═O)SR¹¹, halogen (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R^(3′) is H, —OR¹¹, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl; each R⁴ is independently H, —OR¹¹,NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(ONR¹¹R¹², N₃, CN, NO₂,SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,NR¹¹C(═NR¹¹)NR¹¹R¹², halogen (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl; and each R^(4′) is independently H, OR¹¹(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₄ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; or two R⁴ onadjacent carbon atoms, when taken together, may form a double bondbetween the two carbons to which they are attached or may form a(C₃-C₇)cycloalkyl ring wherein one carbon atom of said (C₃-C₇)cycloalkylring may be optionally replaced by —O—, —S—, —S(O)_(p)—, —NH— or—NR^(a)—; or two R⁴ on non-adjacent carbon atoms, when taken together,may form a (C₃-C₇)cycloalkyl ring wherein one carbon atom of said(C₃-C₇)cycloalkyl ring may be optionally replaced by —O—, —S—,—S(O)_(p)—, —NH— or —NR^(a)—; or two R⁴ and two R^(4′) on adjacentcarbon atoms, when taken together, may form an optionally substituted C₆aryl ring; or one R⁴ and one R^(4′) on the same carbon atom, when takentogether, may form a (C₃-C₇)cycloalkyl ring wherein one carbon atom ofsaid (C₃-C₇)cycloalkyl ring may be optionally replaced by —O—, —S—,—S(O)_(p)—, —NH— or —NR^(a)—; each R⁵ is independently H, —OR¹¹,NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(ONR¹¹R¹², N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═ONR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; each R^(5′) isindependently H, —OR¹¹ (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,aryl(C₃-C₇)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl; each R⁶ is independently H, oxo, OR¹¹,NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(ONR¹¹R¹², N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; or two R⁶ onadjacent carbon atoms, when taken together, may form a (C₃-C₇)cycloalkylring wherein one carbon atom of said (C₃-C₇)cycloalkyl ring may beoptionally replaced by —O—, —S—, —S(O)_(p)—, —NH— or —NR^(a)—; or any R⁶adjacent to the obligate carbonyl group of said Ar, when taken togetherwith R³, may form a bond or a —(CR⁵R^(5′))_(m)— group wherein m is 1 or2; or any R⁶ adjacent to the obligate carbonyl group of said Ar, whentaken together with R² or R^(2′) may form a bond; R⁷ is H, OR¹¹,NR¹¹R¹², NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═ONR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R⁸ is H, OR¹¹,NR¹¹R¹², NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═ONR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R^(8′) is H, —OR¹¹,NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R₂, N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═ONR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; each R^(a) isindependentl (C₁-C₈)alkyl(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl wherein an (C₁-C₈)alkyl(C₁-C₈)haloalkyl,(C₂-C₈)alkenyl or (C₂-C₈)alkynyl of R is optionally substituted with oneor more OH, NH₂, CO₂H, C₂-C₂₀ heterocyclyl, and wherein anyaryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl of R^(a) is optionally substituted withone or more —OH, —NH₂, CO₂H, C₂-C₂₀ heterocyclyl or (C₁-C₈)alkyl; eachR¹¹ or R¹² is independently H (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₈)alkyl, —C(═O)R^(a) or—S(O)_(p)R^(a); or when R¹¹ and R¹² are attached to a nitrogen they mayoptionally be taken together with the nitrogen to which they are bothattached to form a 3 to 7 membered heterocyclic ring wherein any onecarbon atom of said heterocyclic ring can optionally be replaced with—O—, —S—, —S(O)_(p)—, —NIH—, —NR^(a)- or —C(O)—; R¹³ is H or(C₁-C₈)alkyl; R¹⁴ is H (C₁-C₈)alkyl, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,NR¹¹C(ONR¹¹R¹², NR¹¹S(O)_(p)R^(a), —NR¹¹S(O)_(p)(OR¹¹) orNR¹¹SO_(p)NR¹¹R¹²; and wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl of each R¹, R², R^(2′), R³, R^(3′), R⁴,R^(4′), R⁵, R^(5′), R⁶, R⁷, R⁸, R^(8′), R¹¹ or R¹² is independently,optionally substituted with one or more oxo, halogen, hydroxy, —NH₂, CN,N₃, —N(R^(a))₂, —NHR^(a), —SH, —SR^(a), —S(O)_(p)R^(a), —OR^(a)(C₁-C₈)alkyl(C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR^(a)S(O)_(p)N(R^(a))₂,—NR^(a)S(O)_(p)NH₂, —NHS(O) NHR^(a), —NHS(O)_(p)N(R^(a))₂,—NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).
 2. The method ofclaim 1 wherein: a) Y¹ is N, NH or CH, Y² is C, Y³ is N or CR^(8′), Y⁴is N or C and Y⁵ is N, NR^(2′) or CR², wherein at least two of Y¹, Y²,Y³, Y⁴ and Y⁵ are independently N, NH or NR^(2′); or b) Y¹ is N, NH orCH, Y² is N or C, Y³ is N or CR, Y⁴ is N or C, and Y⁵ is N or NR^(2′),wherein at least two of Y¹, Y², Y³, Y⁴, and Y⁵ are independently N, NHor NR²; or c) Y¹ is N, NH or CH, Y² is N or C, Y³ is CR^(8′), Y⁴ is N orC, and Y⁵ is N, NR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴and Y⁵ are independently N, NH or NR^(2′); the dashed bonds ---- areselected from single bonds and double bonds so as to provide an aromaticring system; A is —(CR⁴ R^(4′))_(n)— wherein any one CR⁴R^(4′) of said—(CR⁴R^(4′))_(n)— may be optionally replaced with —O—, —S—, —S(O)_(p)—,NH or NR^(a); n is 3, 4, 5 or 6; each p is 1 or 2; Ar is a C₂-C₂₀heterocyclyl group or a C₆-C₂₀ aryl group, wherein the C₂-C₂₀heterocyclyl group or the C₆-C₂₀ aryl group is optionally substitutedwith 1 to 5 R⁶; X is —C(R¹³)(R¹⁴)—, —N(CH₂R¹⁴)— or —NH—, or X is absent;R¹ is H, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃,CN, NO₂, —SR¹¹, —S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R² is H, CN, NO₂,halogen or (C₁-C₈)alkyl; R^(2′) is H or (C₁-C₈)alkyl; R³ is H, OR¹¹,NR¹¹R¹², NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R^(3′) is H, —OR¹¹,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; each R⁴ isindependently H, OR¹¹, —NR¹¹R¹², NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹,—NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹),—SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹²,NR¹¹C(═NR¹¹)NR¹¹R¹², halogen (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl; and each R^(4′) is independently H, OR¹¹,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; each R⁶ isindependently H, oxo, OR¹¹, NR¹¹R¹², NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹,—NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂, —SR¹¹, —S(O)_(p)R^(a),—NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹², —NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹²,—NR¹¹C(═NR¹¹)NR¹¹R¹², halogen (C₁-C₈)alkyl, (C₁-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R⁷ is H, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹,—NR¹¹C(OR¹¹), —NR¹¹C(O)NR¹¹R¹², N₃, CN, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R⁸ is H, —OR¹¹,NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), —NR¹¹S(O)_(p)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; R^(8′) is H, OR¹¹,NR¹¹R¹², —NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, —NR¹¹C(O)NR¹¹R¹², N₃, CN, NO₂,—SR¹¹, —S(O)_(p)R^(a), NR¹¹S(O)_(p)R^(a), —C(O)R¹¹, —C(O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)_(p)(OR¹¹), —SO₂NR¹¹R¹²,—NR¹¹S(O)_(p)(OR¹¹), —NR¹¹SO_(p)NR¹¹R¹², —NR¹¹C(═NR¹¹)NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C2-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀aryl, C₂-C₂₀ heterocyclyl, C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₈)alkyl; each R^(a) isindependently (C₁-C₈)alkyl(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl wherein any (C₁-C₈)alkyl(C₁-C₈)haloalkyl,(C₂-C₈)alkenyl or (C₂-C₈)alkynyl of R^(a) is optionally substituted withone or more OH, NH₂, CO₂H, C₂-C₂₀ heterocyclyl, and wherein anyaryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl of R^(a) is optionally substituted withone or more —OH, —NH₂, CO₂H, C₂-C₂₀ heterocyclyl or (C₁-C₈)alkyl; eachR¹¹ or R¹² is independently H (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₈)alkyl, —C(═O)R^(a) or—S(O)_(p)R^(a)— or when R¹¹ and R¹² are attached to a nitrogen they mayoptionally be taken together with the nitrogen to which they are bothattached to form a 3 to 7 membered heterocyclic ring wherein any onecarbon atom of said heterocyclic ring can optionally be replaced with—O—, —S—, —S(O)_(p)—, —NH—, —NR^(a)- or —C(O)—; R¹³ is H or(C₁-C₈)alkyl; R¹⁴ is H (C₁-C₈)alkyl, NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,NR¹¹C(O)NR¹¹R¹², NR¹¹S(O)_(p)R^(a), —NR¹¹S(O)_(p)(OR¹¹) orNR¹¹SO_(p)NR¹¹R¹²; and wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyl,C₂-C₂₀ heterocyclyl(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl or(C₃-C₇)cycloalkyl(C₁-C₈)alkyl of each R¹, R², R^(2′), R³, R^(3′), R⁴,R^(4′), R⁶, R⁷, R⁸, R^(8′), R¹¹ or R¹² is independently, optionallysubstituted with one or more oxo, halogen, hydroxy, —NH₂, CN, N₃,—N(R^(a))₂, —NHR^(a), —SH, —SR^(a), —S(O)_(p)R^(a), —OR^(a)(C₁-C₈)alkyl(C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NRS(O)_(p)R^(a), —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR^(a)S(O)_(p)(R^(a))₂,—NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR^(a), —NHS(O)_(p)N(R^(a))₂,—NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).
 3. The method ofclaim 1 wherein the compound of formula I is a compound of formula Ic:

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1wherein R³ and R^(3′) are each H.
 5. The method of claim 1 wherein n is3.
 6. The method of claim 1 wherein each R⁴ and each R^(4′) is H.
 7. Themethod of claim 1 wherein A is —(CH₂)₃—.
 8. The method of claim 1wherein a) Y¹ is N, NH or CH, Y² is C, Y³ is N, Y⁴ is N or C and Y⁵ isNR^(2′) or CR², wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently N, NH or NR^(2′); or b) Y¹ is N, NH or CH, Y² is N or C,Y³ is N or CR^(8′), Y⁴ is N or C, and Y⁵ is N, wherein at least two ofY¹, Y², Y³, Y⁴ and Y⁵ are independently N or NH; or c) Y¹ is N, NH orCH, Y² is N or C, Y³ is CR^(8′), Y⁴ is N or C, and Y⁵ is NR^(2′) or CR²,wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ are independently N, NH orNR^(2′).
 9. The method of claim 1 wherein a) Y¹ is N, Y² is C, Y³ is N,Y⁴ is N and Y⁵ is CR²; or b) Y¹ is N, Y² is N, Y³ is CR^(8′), Y⁴ is C,and Y⁵ is CR².
 10. The method of claim 1 wherein R^(2′), R² and R^(8′)are each H.
 11. The method of claim 1 wherein the compound of formula Iis a compound of formula Ix4:

wherein Z is selected from the group of:

or a salt thereof.
 12. The method of claim 1 wherein the compound offormula I is a compound of formula Im:

or a salt thereof.
 13. The method of claim 12 wherein R² is H.
 14. Themethod of claim 1 wherein X is —C(R¹³)(R¹⁴)— or X is absent.
 15. Themethod of claim 1 wherein R¹³ is H and R¹⁴ is —NHS(O)₂(C₁-C₃)alkyl. 16.The method of claim 1 wherein X is absent.
 17. The method of claim 1wherein R⁷ is H or (C₁-C₈)alkyl, wherein (C₁-C₈)alkyl is optionallysubstituted with one or more oxo, halogen, hydroxy, —NH₂, CN, N₃,—N(R^(a))₂, —NHR^(a), —SH, —SR^(a), S(O)_(p)R^(a), —OR^(a),(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a), —NRC(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NRC(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂, —NR^(a)C(O)NH₂,—NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, ═NH, ═NOH, ═NOR^(a),—NR^(a)S(O)_(p)NHR^(a), —NR¹¹S(O)_(p)N(R^(a))₂, —NR^(a)S(O)_(p)NH₂,—NHS(O)_(p)NHR^(a), —NHS(O)_(p)N(R^(a))₂, —NHS(O)_(p)NH₂, —OC(═O)R^(a),—OP(O)(OH)₂ or R^(a).
 18. The method of claim 1 wherein R⁷ is H ormethyl.
 19. The method of claim 1 wherein R¹ is H, —NR¹¹R¹²,(C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl wherein (C₁-C₈)alkyl or C₂-C₂₀heterocyclyl is optionally substituted with one or more oxo, halogen,hydroxy, —NH₂, CN, N₃, —N(R^(a))₂, —NHR^(a), —SH, —SR^(a),—S(O)_(p)R^(a), —OR^(a), (C₁-C₈)alkyl(C₁-C₈)haloalkyl, —C(O)R^(a),—C(O)H, —C(═O)OR^(a), —C(═)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a),—C(═O)NH₂, NHS(O)_(p)R^(a), —NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a),—NR^(a)C(O)R^(a), —NHC(O)OR^(a), —NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a),—NR^(a)C(O)N(R^(a))₂, —NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂,—NHC(O)NH₂, ═NH, ═NOH, ═NOR^(a), —NR^(a)S(O)_(p)NHR^(a),—NR^(a)S(O)_(p)N(R^(a))₂, —NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR^(a),—NHS(O)_(p)N(R^(a)), —NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).20. The method of claim 1 wherein R¹ is H, (C₁-C₃)alkyl or —NR¹¹R¹²,wherein each R¹¹ or R¹² is independently H or (C₁-C₃)alkyl; or R¹¹ andR¹² together with the nitrogen to which they are both attached to form a3 to 7 membered heterocyclic ring wherein any one carbon atom of saidheterocyclic ring can optionally be replaced with —O—, —S—, —S(O)_(p)—,—NH—, —NR^(a) or —C(O)—.
 21. The method of claim 1 wherein R¹ is H,methyl or azetidinyl.
 22. The method of claim 1 wherein R⁸ is NR¹¹R¹²,(C₁-C₈)alkyl or C₂-C₂₀ heterocyclyl wherein (C₁-C₈)alkyl or C₂-C₂₀heterocyclyl is optionally substituted with one or more oxo, halogen,hydroxy, —NH₂, CN, N₃, —N(R^(a))₂, —NHR^(a), —SH, —SR^(a),—S(O)_(p)R^(a), —OR^(a), (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, —C(O)R^(a),—C(O)H, —C(═O)OR^(a), —C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a),—C(═O)NH₂, —NHS(O)_(p)R^(a), —NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a),—NR^(a)C(O)R¹, —NHC(O)OR^(a), —NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a),—NR^(a)C(O)N(R^(a))₂, —NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂,—NHC(O)NH₂, ═NH, ═NOH, ═NOR^(a), —NR^(a)S(O)_(p)NHR^(a),—NR^(a)S(O)_(p)N(R^(a))₂, —NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR^(a),—NHS(O)_(p)N(R^(a))₂, —NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ orR_(a).
 23. The method of claim 1 wherein R⁸ (C₁-C₈)alkyl, azetidinyl orpyrrolidinyl, wherein azetidinyl or pyrrolidinyl is optionallysubstituted with one or more oxo, halogen, hydroxy, —NH₂, CN, N₃,—N(R^(a))₂, —NHR^(a), —SH, —SR^(a), —S(O)_(p)R^(a), —OR^(a),(C₁-C₈)alkyl (C₁-C₈)haloalkyl, —C(O)R^(a), —C(O)H, —C(═O)OR^(a),—C(═O)OH, —C(═O)N(R^(a))₂, —C(═O)NHR^(a), —C(═O)NH₂, —NHS(O)_(p)R^(a),—NR^(a)S(O)_(p)R^(a), —NHC(O)R^(a), —NR^(a)C(O)R^(a), —NHC(O)OR^(a),—NR^(a)C(O)OR^(a), —NR^(a)C(O)NHR^(a), —NR^(a)C(O)N(R^(a))₂,—NR^(a)C(O)NH₂, —NHC(O)NHR^(a), —NHC(O)N(R^(a))₂, —NHC(O)NH₂, —NH, —NOH,═NOR^(a), —NR^(a)S(O)_(p)NHR^(a), —NR^(a)S(O)_(p)N(R^(a))₂,—NR^(a)S(O)_(p)NH₂, —NHS(O)_(p)NHR^(a), —NHS(O)_(p)N(R^(a))₂,—NHS(O)_(p)NH₂, —OC(═O)R^(a), —OP(O)(OH)₂ or R^(a).
 24. The method ofclaim 1 wherein R⁸ is methyl, azetidinyl or pyrrolidinyl, whereinazetidinyl or pyrrolidinyl is optionally substituted with one or morehydroxy, NH₂ or CN.
 25. The method of claim 1 wherein Ar is a phenyl or5-6 membered monocyclic heteroaryl, wherein phenyl or 5-6 memberedmonocyclic heteroaryl is optionally substituted with 1 to 5 R⁶.
 26. Themethod of claim 1 wherein Ar is a phenyl, pyridinyl or thienyl, whereinphenyl, pyridinyl or thienyl is optionally substituted with 1 to 5 R⁶.27. The method of claim 1 wherein each R⁶ is —NR¹¹S(O)_(p)R^(a),halogen, or (C₁-C₈)alkyl.
 28. The method of claim 1 wherein each R⁶ is—NHS(O)₂CH₃, chloro, bromo or methyl.
 29. The method of claim 1 selectedfrom:

and pharmaceutically acceptable salts thereof.
 30. The method selectedfrom:

and pharmaceutically acceptable salts thereof.
 31. (canceled) 32.(canceled)
 33. (canceled)
 34. (canceled)
 35. (canceled)
 36. (canceled)37. (canceled)
 38. (canceled)
 39. The method of claim 1 wherein thePneumovirinae virus infection is caused by a respiratory syncytialvirus.
 40. The method of claim 1 further comprising administering atherapeutically effective amount of at least one other therapeutic agentselected from the group consisting of ribavirin, palivizumab,motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV01and ALX-0171 and mixtures thereof.